Indoline derivatives

ABSTRACT

This invention relates to substituted indoline derivative compounds which are antagonists of the progesterone receptor, their preparation and pharmaceutical utility, particularly including contraception and treatment of benign or malignant neoplastic diseases, having the general structure: 
                         
wherein R 1  and R 2  may be single substituents or fused to form spirocyclic rings.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.11/378,851, filed Mar. 17, 2006, now U.S. Pat. No. 7,253,203, which is adivisional of U.S. patent application Ser. No. 10/456,892, filed Jun. 6,2003, now U.S. Pat. No. 7,084,168, which is a divisional of U.S. patentapplication Ser. No. 10/014,173, filed Dec. 11, 2001, now U.S. Pat. No.6,608,068, which is a divisional of U.S. patent application Ser. No.09/552,632, filed Apr. 19, 2000, now U.S. Pat. No. 6,391,907, whichclaims the benefit of the priority of U.S. patent application Ser. No.60/183,058, filed May 4, 1999.

BACKGROUND OF THE INVENTION

This invention relates to compounds which are antagonists of theprogesterone receptor, their preparation and utility.

Intracellular receptors (IR) form a class of structurally related generegulators known as “ligand dependent transcription factors” (R. M.Evans, Science, 240, 889, 1988). The steroid receptor family is a subsetof the IR family, including progesterone receptor (PR), estrogenreceptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), andmineralocorticoid receptor (MR).

The natural hormone, or ligand, for the PR is the steroid progesterone,but synthetic compounds, such as medroxyprogesterone acetate orlevonorgestrel, have been made which also serve as ligands. Once aligand is present in the fluid surrounding a cell, it passes through themembrane via passive diffusion, and binds to the IR to create areceptor/ligand complex. This complex binds to specific gene promoterspresent in the cell's DNA. Once bound to the DNA the complex modulatesthe production of mRNA and protein encoded by that gene.

A compound that binds to an IR and mimics the action of the naturalhormone is termed an agonist, whilst a compound which inhibits theeffect of the hormone is an antagonist.

PR antagonists may be used in contraception. In this context they may beadministered alone (Ulmann, et al, Ann. N.Y. Acad. Sci., 261, 248,1995), in combination with a PR agonist (Kekkonen, et al, Fertility andSterility, 60, 610, 1993) or in combination with a partial ER antagonistsuch as tamoxifen (WO 96/19997 A1 Jul. 4, 1996).

PR antagonists may also be useful for the treatment of hormone dependentbreast cancers (Horwitz, et al, Horm. Cancer, 283, pub: Birkhaeuser,Boston, Mass., ed. Vedeckis) as well as uterine and ovarian cancers. PRantagonists may also be useful for the treatment of non-malignantchronic conditions such as fibroids (Murphy, et al, J. Clin. Endo.Metab., 76, 513, 1993) and endometriosis (Kettel, et al, Fertility andSterility, 56, 402, 1991).

PR antagonists may also be useful in hormone replacement therapy forpost menopausal patients in combination with a partial ER antagonistsuch as tamoxifen (U.S. Pat. No. 5,719,136).

PR antagonists, such as mifepristone and onapristone, have been shown tobe effective in a model of hormone dependent prostate cancer, which mayindicate their utility in the treatment of this condition in men(Michna, et al, Ann. N.Y. Acad. Sci., 761, 224, 1995).

The compounds of this invention have been shown to act as competitiveinhibitors of progesterone binding to the PR and act as antagonists infunctional models, either/or in-vitro and in-vivo. These compounds maybe used for contraception, in the treatment of fibroids, endometriosis,breast, uterine, ovarian and prostate cancer, and post menopausalhormone replacement therapy.

Described by Jones, et al, (U.S. Pat. No. 5,688,810) is the PRantagonist dihydroquinoline A.

Jones, et al. described the enol ether B (U.S. Pat. No. 5,693,646) as aPR ligand.

Jones, et al. described compound C (U.S. Pat. No. 5,696,127) as a PRligand.

Zhi, et al. described lactones D, E and F as PR antagonists (J. Med.Chem., 41, 291, 1998).

Zhi, et al. described the ether G as a PR antagonist (J. Med. Chem., 41,291, 1998).

Combs, et al. disclosed the amide H as a ligand for the PR (J. Med.Chem., 38, 4880, 1995).

Perlman, et al. described the vitamin D analog I as a PR ligand (Tet.Letters, 35, 2295, 1994).

Hamann, et al. described the PR antagonist J (Ann. N.Y. Acad. Sci., 761,383, 1995).

Chen, et al. described the PR antagonist K (Chen, et al, POI-37, 16^(th)Int. Cong. Het. Chem., Montana, 1997).

Kurihari, et. al. described the PR ligand L (J. Antibiotics, 50, 360,1997).

Kuhla, et al. disclosed the oxindole M as having cardiotonic activity(WO 86/03749).

Weber teaches the oxindole N for cardiovascular indications (WO91/06545).

Fischer, et al. describe a preparation for making compounds whichinclude the generic structure O (U.S. Pat. No. 5,453,516).

Singh, et al. described the PDE III inhibitor P (J. Med. Chem., 37, 248,1994).

Andreani, et al. described the cytotoxic agent Q (Acta. Pharm. Nord., 2,407, 1990).

Binder, et al. described structure R which is an intermediate forpreparing COX II inhibitors (WO 97/13767).

Walsh described the oxindole S as an intermediate (U.S. Pat. No.4,440,785, U.S. Pat. No. 4,670,566).

Bohm, et al. claim the oxindole T as cardiovascular agents (WO91/06545).

Bohm, et al. include the generic structure U (WO 91/04974).

JP 63112584 A contains the generic structure V:

Boar, et al. described the dioxolane W as an intermediate forpreparation of acetyl-cholinesterase inhibitors (WO 93/12085 A1).

Kende, et al. described methodology for preparing 3,3-substitutedoxindoles, e.g. X, that was utilized in the present invention (Synth.Commun., 12, 1, 1982).

DESCRIPTION OF THE INVENTION

This invention comprises compounds of the Formula 1:

wherein:

R₁ and R₂ are chosen independently from H, alkyl, substituted alkyl; OH;O(alkyl); O(substituted alkyl); OAc; aryl; optionally substituted aryl;heteroaryl; optionally substituted heteroaryl; alkylaryl;alkylheteroaryl; 1-propynyl; or 3-propynyl;

or R₁ and R₂ are joined to form a ring comprising one of the following:—CH₂(CH₂)_(n)CH₂—; —CH₂CH₂CMe₂CH₂CH₂—; —O(CH₂)_(m)CH₂—; O(CH₂)_(p)O;—CH₂CH₂OCH₂CH₂—; or —CH₂CH₂N(H or alkyl)CH₂CH₂—;

or R₁ and R₂ comprise a double bond to CMe₂, C(cycloalkyl), O, orC(cycloether);

n is an integer from 0 to 5;

m is an integer from 1 to 4;

p is an integer from 1 to 4;

R₃ is selected from H, OH, NH₂, C₁ to C₆ alkyl, substituted C₁ to C₆alkyl, C₃ to C₆ alkenyl, alkynyl or substituted alkynyl, or COR^(A);

R^(A) is selected from H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, C₁to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, orsubstituted C₁ to C₃ aminoalkyl;

R⁴ is selected from H, halogen, CN, NH₂, C₁ to C₆ alkyl, substituted C₁to C₆ alkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆aminoalkyl, or substituted C₁ to C₆ aminoalkyl;

R⁵ is selected from the groups a), b) or c):

a) R⁵ is a trisubstituted benzene ring containing the substituents X, Yand Z as shown below:

wherein:

X is selected from the group of halogen, OH, CN, C₁ to C₃ alkyl,substituted C₁ to C₃ alkyl, C₁ to C₃ alkoxy, substituted C₁ to C₃alkoxy, C₁ to C₃ thioalkyl, substituted C₁ to C₃ thioalkyl, S(O)alkyl,S(O)₂alkyl, C₁ to C₃ aminoalkyl, substituted C₁ to C₃ aminoalkyl, NO₂,C₁ to C₃ perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1to 3 heteroatoms, COR^(B), OCOR^(B), or NR^(C)COR^(B);

R^(B) is H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl,substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, or substituted C₁ to C₃ aminoalkyl;

R^(C) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃ alkyl;

Y and Z are independently selected from H, halogen, CN, NO₂, C₁ to C₃alkoxy, C₁ to C₃ alkyl, or C₁ to C₃ thioalkyl; or

b) R⁵ is a five or six membered heterocyclic ring with 1, 2, or 3heteroatoms selected from O, S, SO, SO₂ or NR⁶ and containing one or twoindependent substituents from the group of H, halogen, CN, NO₂ and C₁ toC₃ alkyl, C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, COR^(D), orNR^(E)COR^(D);

R^(D) is H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl,substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, or substituted C₁ to C₃ aminoalkyl;

R^(E) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃ alkyl;

R⁶ is H, or C₁ to C₃ alkyl; or

c) R⁵ is an indol-4-yl, indol-7-yl or benzo-2-thiophene moiety, themoiety being optionally substituted by from 1 to 3 substituents selectedfrom halogen, lower alkyl, CN, NO₂, lower alkoxy, or CF₃;

or a pharmaceutically acceptable salt thereof.

A preferred set of compounds of this invention is depicted by structure2, 2a:

wherein:

R⁵ is a disubstituted benzene ring containing the substituents X and Yas shown below:

X is taken from the group of halogen, CN, C₁ to C₃ alkoxy, C₁ to C₃alkyl, NO₂, C₁ to C₃ perfluoroalkyl, 5 membered heterocyclic ringcontaining 1 to 3 heteroatoms or C₁ to C₃ thioalkoxy;

Y is a substituent on the 4′ or 5′position of the disubstituted benzenering selected from the group of H, halogen, CN, NO₂, C₁ to C₃ alkoxy, C₁to C₄ alkyl, or C₁ to C₃ thioalkyl;

or a pharmaceutically acceptable salt thereof.

Another preferred group of this invention comprises compounds offormulas 2 and 2a wherein R⁵ is a five membered ring with the structureshown below:

U is O, S, or NR⁶;

R⁶ is H, or C₁ to C₃ alkyl, C₁ to C₄ CO₂alkyl;

X′ is selected from the group of halogen, CN, NO₂, C₁ to C₃ alkyl or C₁to C₃ alkoxy; with a proviso that, when X′ is CN, U is not NR⁶;

Y′ is selected from H, F, CN, NO₂ or C₁ to C₄ alkyl;

or a pharmaceutically acceptable salt thereof.

Another preferred group of formulas 2 and 2a are those in which R⁵ is asix membered ring with the structure shown

wherein:

X¹ is N or CX²;

X² is halogen, CN or NO₂;

or pharmaceutically acceptable salt thereof.

The compounds of this invention may contain an asymmetric carbon atomand some of the compounds of this invention may contain one or moreasymmetric centers and may thus give rise to optical isomers anddiastereomers. While shown without respect to stereochemistry in Formula1 and 2 the present invention includes such optical isomers anddiastereomers; as well as the racemic and resolved, enantiomericallypure R and S stereoisomers; as well as other mixtures of the R and Sstereoisomers and pharmaceutically acceptable salts thereof.

The term “alkyl” is used herein to refer to both straight- andbranched-chain saturated aliphatic hydrocarbon groups having 1 to 8carbon atoms; “alkenyl” is intended to include both straight- andbranched-chain alkyl groups with 1 or 2 carbon-carbon double bonds andcontaining 2 to 8 carbon atoms; “alkynyl” group is intended to coverboth straight- and branched-chain alkyl groups with at least 1 or 2carbon-carbon triple bonds and containing 2 to 8 carbon atoms.

The terms “substituted alkyl”, “substituted alkenyl”, and “substitutedalkynyl” refer to alkyl, alkenyl, and alkynyl as just described havingone or more substituents from the group including halogen, CN, OH, NO₂,amino, aryl, heterocyclic, substituted aryl, substituted heterocyclic,alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy,alkylamino, and arylthio. These substituents may be attached to anycarbon of an alkyl, alkenyl, or alkynyl group provided that theattachment constitutes a stable chemical moiety.

The term “aryl” is used herein to refers to an aromatic system which maybe a single ring or multiple aromatic rings fused or linked together assuch that at least one part of the fused or linked rings forms theconjugated aromatic system. The aryl groups include, but are not limitedto, phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, andphenanthryl.

The term “substituted aryl” refers to aryl as just defined having 1 to 4substituents from the group including halogen, CN, OH, NO₂, amino,alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substitutedalkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.

The term “heterocyclic” is used herein to describe a stable 4- to7-membered monocyclic or a stable multicyclic heterocyclic ring which issaturated, partially unsaturated, or unsaturated, and which consists ofcarbon atoms and from one to four heteroatoms selected from the groupincluding N, O, and S atoms. The N and S atoms may be oxidized. Theheterocyclic ring also includes any multicyclic ring in which any ofabove defined heterocyclic rings is fused to an aryl ring. Theheterocyclic ring may be attached at any heteroatom or carbon atomprovided the resultant structure is chemically stable. Such heterocyclicgroups include, but are not limited to, tetrahydrofuran, piperidinyl,piperazinyl, 2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl,morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl,benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, andisoquinolinyl.

The term “substituted heterocyclic” is used herein to describe theheterocyclic just defined having 1 to 4 substituents selected from thegroup which includes halogen, CN, OH, NO₂, amino, alkyl, substitutedalkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy,aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino,or arylthio.

The term “thioalkyl” is used herein to refer to the SR group, where R isalkyl or substituted alkyl, containing 1 to 8 carbon atoms, preferably 1to 6 carbon atoms. The term “alkoxy” is used herein to refer to the ORgroup, where R is alkyl or substituted alkyl, containing 1 to 8 carbonatoms, preferably 1 to 6 carbon atoms. The term “aryloxy” is used hereinto refer to the OR group, where R is aryl or substituted aryl, asdefined above. The term “alkylcarbonyl” is used herein to refer to theRCO group, where R is alkyl or substituted alkyl, containing 1 to 8carbon atoms, preferably 1 to 6 carbon atoms. The term “alkylcarboxy” isused herein to refer to the COOR group, where R is alkyl or substitutedalkyl, containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms.The term “aminoalkyl” refers to both secondary and tertiary amineswherein the alkyl or substituted alkyl groups, containing 1 to 8 carbonatoms, preferably 1 to 6 carbon atoms, which may be either the same ordifferent and the point of attachment is on the nitrogen atom. The term“halogen” refers to Cl, Br, F, or I.

The compounds of this invention may be prepared according to the methodsdescribed below.

According to scheme 1, commercially available oxindole 5 is treated witha mixture of a strong organo-metallic base (e.g. butyl lithium, lithiumdiisopropylamide, potassium hexamethyldisilazide) in an inert solvent(e.g. THF, diethyl ether) under nitrogen at reduced temperature (ca.−20° C.) (Kende, et al, Synth. Commun., 12, 1, 1982). The resultingdi-anion is then treated with excess electrophile such as an alkylhalide, preferably the iodide. If R₁ and R₂ are to be joined such as theproduct 6 contains a spirocycle at position 3, then the electrophileshould be bifunctional, i.e. a diiodide. Subsequent bromination of 6proceeds smoothly with bromine in acetic acid (an organic co-solventsuch as dichloromethane may be added as required) in the presence ofsodium acetate, to afford the aryl bromide 7. The bromide 7 is reactedwith a palladium salt (e.g. tetrakis(triphenylphoshine)palladium0)), ina suitable solvent (e.g. THF, dimethoxyethane, ethanol, toluene) at roomtemperature under an inert atmosphere (argon, nitrogen). The mixture isthen treated with an arylboronic acid or boronic acid ester and a base(sodium carbonate, triethylamine, potassium phosphate) in water orfluoride source (cesium fluoride) under anhydrous conditions. Therequired product 8 is then isolated and purified by standard means.

If R₁ and R₂ are different, then the intermediate 6 is prepared byreacting the dianion of 5 with one equivalent of the electrophile R₁—X(X=leaving group e.g. I). The resultant mono-alkylated compound may bethen isolated and re-subjected to the reaction conditions using R₂—X, oralternatively used in-situ for the second alkylation with R₂—X.Alternatively if the desired product 8 is to contain R₂═H, then theisolated mono-alkylated intermediate is taken through the subsequentsteps.

Other methodologies are also available for coupling the pendant arylgroup, Ar, to the oxindole platform, for example reaction of compound 7with an aryl stannane, aryl zinc, or aryl magnesium halide in thepresence of a palladium or nickel catalyst (scheme 2). The requiredaryl-metallic species described above are formed through standardtechniques.

Other functionalities can easily be installed into the 3-position of theindoline platform according to scheme 3. Oxidation of the unsubstitutedindoline 9, preferably under neutral or acidic conditions (e.g. seleniumdioxide in dry dioxane at reflux) affords the isatin 10. Compound 10 maybe further functionalized to provide a ketal 11 by treatment with analcohol and acid catalyst under dehydrating conditions. Alternativelyreaction of 10 with a second ketone under suitable conditions(piperidine in toluene at reflux; or TiCl₄/Zn in THF at reflux) affordsalkylidene derivatives 12. Reaction of the isatin 10 with a grignardreagent or organolithium affords tertiary alcohols 13 (R═H). Thesealcohols may then be further functionalized by alkylation or acylationprocedures.

Treatment of the bromide 7 in an anhydrous solvent (e.g. THF, Et₂O) witha strong base (sodium hydride preferred, sodium hexamethyldisilazide,potassium hydride) followed by reaction at reduced temperature (−50 to−20° C.) with n-butyllithium and N,N,N,N′-tetramethylethylenediaminefollowed after a suitable period of time by a trialkylborate (trimethylor triisopropylborate) gives after acidic work-up the boronic acid 14(scheme 4). Compound 14 may then be reacted under palladium catalyzedconditions tetrakis(triphenylphosphine)palladium(0), base (NaHCO₃,Na₂CO₃, K₂CO₃, triethylamine, CsF) solvent (toluene/EtOH/water,THF/water, dimethoxyethane/water, anhydrous dimethoxyethane) with anaryl bromide, aryl iodide, aryltrifluoromethane sulfonate of arylfluorosulfonate, to provide the desired compounds 8.

An alternative strategy would be to prepare an organo zinc or magnesiumreagent from compound 7 and react it in-situ with an aryl bromide, aryliodide, aryltrifluoromethane sulfonate of arylfluorosulfonate, underpalladium catalyzed conditions to afford compound 8. Such an organo zincor magnesium species could be prepared by treatment of the bromide 7 inan anhydrous solvent (e.g. THF, Et₂O) with a strong base (sodium hydridepreferred, sodium hexamethyldisilazide, potassium hydride) followed byreaction at reduced temperature (−50 to −20° C.) with n-butyllithium andN,N,N′,N′-tetramethylethylenediamine followed after a suitable period oftime by reaction with anhydrous zinc chloride or magnesium bromide.

The compounds of the present invention can be used in the form of saltsderived from pharmaceutically or physiologically acceptable acids orbases. These salts include, but are not limited to, the following saltswith inorganic acids such as hydrochloric acid, sulfuric acid, nitricacid, phosphoric acid and, as the case may be, such organic acids asacetic acid, oxalic acid, succinic acid, and maleic acid. Other saltsinclude salts with alkali metals or alkaline earth metals, such assodium, potassium, calcium or magnesium in the form of esters,carbamates and other conventional “pro-drug” forms, which, whenadministered in such form, convert to the active moiety in vivo.

This invention includes pharmaceutical compositions and treatments whichcomprise administering to a mammal a pharmaceutically effective amountof one or more compounds as described above as antagonists of theprogesterone receptor.

The progesterone receptor antagonists of this invention, used alone orin combination, can be utilized in methods of contraception and thetreatment and/or prevention of benign and malignant neoplastic disease.Specific uses of the compounds and pharmaceutical compositions ofinvention include the treatment and/or prevention of uterine myometrialfibroids, endometriosis, benign prostatic hypertrophy; carcinomas andadenocarcinomas of the endometrium, ovary, breast, colon, prostate,pituitary, meningioma and other hormone-dependent tumors. Additionaluses of the present progesterone receptor antagonists include thesynchronization of the estrus in livestock.

When the compounds are employed for the above utilities, they may becombined with one or more pharmaceutically acceptable carriers orexcipients, for example, solvents, diluents and the like, and may beadministered orally in such forms as tablets, capsules, dispersiblepowders, granules, or suspensions containing, for example, from about0.05 to 5% of suspending agent, syrups containing, for example, fromabout 10 to 50% of sugar, and elixirs containing, for example, fromabout 20 to 50% ethanol, and the like, or parenterally in the form ofsterile injectable solutions or suspensions containing from about 0.05to 5% suspending agent in an isotonic medium. Such pharmaceuticalpreparations may contain, for example, from about 25 to about 90% of theactive ingredient in combination with the carrier, more usually betweenabout 5% and 60% by weight.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration and theseverity of the condition being treated. However, in general,satisfactory results are obtained when the compounds of the inventionare administered at a daily dosage of from about 0.5 to about 500 mg/kgof animal body weight, preferably given in divided doses two to fourtimes a day, or in a sustained release form. For most large mammals, thetotal daily dosage is from about 1 to 100 mg, preferably from about 2 to80 mg. Dosage forms suitable for internal use comprise from about 0.5 to500 mg of the active compound in intimate admixture with a solid orliquid pharmaceutically acceptable carrier. This dosage regimen may beadjusted to provide the optimal therapeutic response. For example,several divided doses may be administered daily or the dose may beproportionally reduced as indicated by the exigencies of the therapeuticsituation.

These active compounds may be administered orally as well as byintravenous, intramuscular, or subcutaneous routes. Solid carriersinclude starch, lactose, dicalcium phosphate, microcrystallinecellulose, sucrose and kaolin, while liquid carriers include sterilewater, polyethylene glycols, non-ionic surfactants and edible oils suchas corn, peanut and sesame oils, as are appropriate to the nature of theactive ingredient and the particular form of administration desired.Adjuvents customarily employed in the preparation of pharmaceuticalcompositions may be advantageously included, such as flavoring agents,coloring agents, preserving agents, and antioxidants, for example,vitamin E, ascorbic acid, BHT and BHA.

The preferred pharmaceutical compositions from the standpoint of ease ofpreparation and administration are solid compositions, particularlytablets and hard-filled or liquid-filled capsules. Oral administrationof the compounds is preferred.

These active compounds may also be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacologically acceptable salt can be prepared inwater suitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid, polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringe ability exits. It must be stable underconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacterial and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), suitable mixtures thereof, and vegetable oil.

The present invention may be further understood by the followingnon-limiting examples.

EXAMPLES Example 1 5-(3-Nitro-phenyl)-1,3-dihydro-indol-2-one5-(Bromo)-1,3-dihydro-indol-2-one

A solution of oxindole (2.0 g, 15.0 mmol) and sodium acetate (2.1 g,25.5 mmol) in CHCl₃ (20 cm³) was treated with bromine (2.4 g, 15.0 mmol)in CHCl₃ (10 cm³). After 30 min. the mixture was allowed to warm to RTand stirred for 1 h. The reaction mixture was diluted with EtOAc (500cm³) and poured into water. The aqueous layer was extracted with EtOAc(×2), the combined organic layers were washed with water, sat. sodiumhydrogen carbonate solution, brine, dried (MgSO₄), and evaporated togive the title compound (3.1 g, 14.6 mmol, 96%) as an off-white solidwhich was used without further purification: m.p. 221-223° C.; ¹H NMR(DMSO-d₆) δ 3.51 (s, 2H), 6.76 (d, 1H, J=8.1 Hz), 7.33 (dd, 1H, J=8.1,1.7 Hz), 7.37 (s, 1H), 10.49 (brs, 1H); ¹³C NMR (DMSO-d₆) δ 36.10 (t),111.21 (d), 113.16 (s), 127.54 (d), 128.3 (s), 130.40 (d), 143.34 (s),176.24 (s); MS (EI) m/z 211, 213 (M)⁺.

5-bromo-2-indolinone (1.08 g, 5.09 mmol) and tetrakistriphenyl phosphinePd(0) (0.273 g) were stirred under an atmosphere of nitrogen in ethyleneglycol dimethyl ether (35 mL). After 15 minutes, 3-nitrophenyl boronicacid (1.70 g, 10.2 mmol) was added, followed by potassium carbonate(4.24 g, 30.7 mmol) in water (15 mL). The reaction was heated to refluxovernight, cooled to room temperature and then filtered. Saturatedammonium chloride was added. The water layer was extracted with ethylacetate (3×20 mL). The combined organic layer was dried with MgSO₄,filtered, and solvent removed in vacuo. The product was purified byflash silica gel chromatography (3:2 hexane; ethyl acetate) to give5-(3-Nitro-phenyl)-1,3-dihydro-indol-2-one (0.084 g, 65%), Mp=269° C.;¹H NMR (DMSO) δ 10.5 (s, 1H), 8.38-8.36 (m, 1H) 8.17-8.14 (m, 1H),8.10-8.07 (m, 1H), 7.75-7.60 (m, 3H), 6.95 (d, 1H, J=8.1 Hz), 3.57 (s,2H); IR (KBr) 3420, 3190, 1700 cm⁻¹; MS (EI) m/z 253 (M−H)⁻; CHNcalculated for C₁₄H₁₀N₂O: C, 66.14; H, 3.96; N, 11.02; Found: C, 64.59;H, 4.16; N, 9.43.

Example 2 3-methyl-5-(3-nitrophenyl)-1,3-dihydroindol-2-one5-bromo-3-methyl-indol-2-one

Under an atmosphere of nitrogen, bromine (0.96 g, 6.0 mmol) in aceticacid (5 cm³) was added drop wise to a solution of 3-methyl-2-indolinone(0.8749 g, 6.0 mmol) (Kende, et al, Synth. Commun., 12, 1, 1982) andsodium acetate (0.50 g, 6.0 mmol) in acetic acid (10 cm³). The reactionwas stirred at room temperature for 3.5 h. Saturated sodium carbonatewas added to quench the reaction. The water layer was extracted withEtOAc (×3), dried (MgSO₄), filtered, and evaporated to give the titlecompound (1.26 g, 93%), Mp=119-120° C.; ¹H NMR (DMSO) δ 1.32 (d, 3H,J=7.66 Hz), 3.45 (q, 1H, J=7.62 Hz), 6.77 (d, 1H, J=8.23 Hz), 7.46 (s,1H), 7.36-7.33 (m, 1H), 10.4 (s, 1H); IR (KBr) 3200, 1725 cm⁻¹; MS (EI)m/z 224/226 (M−H)⁻; CHN calculated for C₉H₈BrNO: C, 47.82; H, 3.57; N,6.20; Found: C, 47.44; H, 3.42; N, 6.04.

5-Bromo-3-methyl-1,3-dihydro-indol-2-one (0.50 g, 2.22 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.15 g) were stirred under anatmosphere of nitrogen in dimethoxyethane (18 cm³). After 15 min.,3-nitrophenyl boronic acid (0.74 g, 4.45 mmol) was added, followed bypotassium carbonate (1.86 g, 13.5 mmol) in water (7 cm³). The reactionwas heated to reflux for 8 h and then stirred at room temperatureovernight. Saturated ammonium chloride was added; and the aqueous layerwas extracted with EtOAc (×3). The combined organic layers were dried(MgSO₄), filtered, and evaporated. The residue was purified by columnchromatography (SiO₂, EtOAc:hexane 1:2); eluted: 2:1 hexane; ethylacetate, to give the title compound (0.30 g, 47%), mp 200-203° C.; ¹HNMR (DMSO-d₆) δ 1.41 (d, 3H, J=7.61 Hz), 3.50 (q, 1H, J=7.60 Hz), 6.96(d, 1H, J=8.08 Hz), 7.62 (d, 1H, J=8.06 Hz), 7.75-7.70 (m, 2H),8.18-8.10 (m, 2H), 8.41-8.39 (m, 1H), 10.5 (s, 1H); IR (KBr) 3450, 1700cm⁻¹; MS (EI) m/z 267 (M−H); Anal. Calc. for C₁₅H₁₂N₂O₃+0.2C₄H₈O₂: C,66.61; H, 4.46; N, 9.83; Found: C, 66.26; H, 4.59; N, 10.06.

Example 3 5-(3-Methoxy-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one5-bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one

3,3-dimethyl-indol-2-one (0.65 g, 4.03 mmol) and sodium acetate (0.33 g,4.07 mmol) were stirred in acetic acid (5 cm³) then bromine (0.66 g,4.13 mmol) in acetic acid (5 cm³) was added drop-wise to the reactionmixture. The reaction was stirred for 50 min., and then poured intowater. The mixture was basified with sodium carbonate and then extractedwith ethyl acetate (×3), dried (MgSO₄), filtered, and evaporated to thetitle compound (0.89 g, 92%) ¹H NMR (DMSO-d₆) δ 1.21 (s, 6H), 6.76 (d,1H, J=8.22 Hz), 7.29 (dd, 1H, J=2.12 Hz, 8.23 Hz), 7.49 (d, 1H, J=2.03Hz), 10.4 (s, 1H).

5-bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (0.33 g, 1.38 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.094 g) were stirred under anatmosphere of nitrogen in dimethoxyethane (12 cm³). After 15 minutes,3-methoxyphenylboronic acid (0.42 g, 2.76 mmol) was added, followed bypotassium carbonate (1.15 g, 8.34 mmol) in water (5 cm³). The reactionwas heated to reflux for 5 hours, and then cooled to room temperature.Saturated aqueous ammonium chloride and EtOAc were added and the mixturewas filtered. The aqueous layer was extracted with EtOAc (×2), and thecombined organic layers were dried (MgSO₄), filtered, and evaporated.The residue was purified by column chromatography (SiO₂, EtOAc:hexane1:3) to afford the title compound (0.11 g, 31%), mp=157-158° C.; ¹H NMR(DMSO-d₆) δ 3.34 (s, 6H), 3.82 (s, 3H), 6.87-6.93 (m, 2H), 7.20-7.15 (m,2H), 7.37-7.32 (m, 1H), 7.49-7.46 (m, 1H), 7.63 (d, 1H, J=1.14 Hz), 10.4(s, 1H); MS (EI) m/z 266 (M−H)⁻; Anal. Calc. for C₁₇H₁₇NO₂: C, 76.38; H,6.41; N, 5.24; Found: C, 76.02; H, 6.49; N, 5.02.

Example 4 5-(3-Chloro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one

5-bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (0.98 g, 4.07 mol) andtetrakis(triphenylphosphine)palladium(0) (0.239 g) were stirred under anatmosphere of nitrogen in dimethoxyethane (35 cm³). After 15 min.,3-chlorophenylboronic acid (1.27 g, 8.13 mol) was added, followed bypotassium carbonate (3.40 g, 45 mmol) in water (15 cm³). The reactionwas heated to reflux for 2 hours and then stirred at room temperatureovernight. The mixture was diluted with sat. ammonium chloride andextracted with EtOAc (×3). The combined organic layers were dried(MgSO₄), filtered, and evaporated. The residue was purified by columnchromatography (SiO₂, EtOAc:hexane, 1:3) to afford the title compound(0.284 g, 25%): mp 188-189° C.; ¹H NMR (DMSO-d₆) δ 3.34 (s, 6H), 6.93(d, 1H, J=8.04 Hz), 7.38-7.35 (m, 1H), 7.53-7.43 (m, 2H), 7.61 (d, 1H,J=7.68 Hz), 7.70 (s, 2H), 10.40 (s, 1H); IR (KBr) 3420, 3150, 3050, 1700cm⁻¹; MS (EI) m/z 270 (M−H)⁻; Anal. Calc. for C₁₆H₁₄ClNO+0.1C₄H₈O₂: C,70.21; H, 5.32; N, 4.99; Found: C, 70.3; H, 5.44; N, 4.93.

Example 5 3,3-Dimethyl-5-(3-nitro-phenyl)-1,3-dihydro-indol-2-one

5-bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (1.02 g, 4.26 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.244 g) were stirred under anatmosphere of nitrogen in dimethoxyethane (35 cm³). After 15 minutes,3-nitrophenylboronic acid (1.43 g, 2.56 mmol) was added, followed bypotassium carbonate (3.54 g, 2.56 mmol) in water (15 cm³). The reactionwas heated to reflux for 2 hours and then stirred at room temperatureovernight. Saturated ammonium chloride and EtOAc were added and themixture was filtered. The aqueous layer was extracted with ethyl acetate(×2), and then the combined organic layers were dried (Na₂SO₄),filtered, and evaporated. The residue was purified by columnchromatography (SiO₂, EtOAc:hexane, gradient elution) to afford thetitle compound (0.86 g, 67%) mp 234-235° C.; ¹H NMR (DMSO-d₆) δ 3.33 (s,6H), 6.98 (d, 1H, J=8.06 Hz), 7.61 (dd, 1H, J=1.85, 8.03 Hz), 7.73 (t,1H, J=7.98 Hz), 7.81 (d, 1H, J=1.63 Hz), 8.11-8.18 (m, 2H), 8.42-8.43(m, 1H), 10.5 (s, 1H); MS (EI) m/z 281; Anal. Calc. forC₁₆H₁₄N₂O₃.0.2H₂O: C, 67.51; H, 4.92; N, 9.37; Found: C, 67.48; H, 5.17;N, 9.48.

Example 6 5-(3-Chloro-phenyl)-3-ethyl-1,3-dihydro-indol-2-one3-Ethyl-indol-2-one

A solution of oxindole (40 g, 0.3 mol) in dry THF (400 ml) under N₂ wascooled to −25° C. and treated drop wise with n-butyl lithium (2.5M inhexanes, 240 ml, 0.6 mol). To the resulting solution was addedN,N,N′,N′-tetramethylethylenediamine (90.4 ml, 0.6 mol). After 30 min.iodoethane (48 ml, 0.6 mol) was added and the reaction mixture wasallowed to warm to RT and stirred over night. The reaction mixture waspoured into aqueous NH₄Cl solution, extracted with EtOAc (2×) and thecombined organic layers were washed with dil. HCl, water, brine, dried(MgSO₄) and concentrated. The residual oil was triturated with hexane toafford the crude product (24.5 g, 51%). A sample (3 g) wasrecrystallized from EtOAc/hexane to obtain the title compound (1.4 g),m.p. 100-101° C.; ¹H-NMR (DMSO-d₆) δ0.76 (t, 3H, J=7.5 Hz), 1.8-2.0 (m,2H), 3.38 (t, 3H, J=5.7 Hz), 6.8 (dt, 1H, J=7.69, 0.45 Hz), 6.93 (dt,1H, J=7.45, 1.10 Hz), 7.15 (m, 1H), 7.22 (m, 1H), 10.3 (s, 1H); MS (ESI)m/z 270 [M+H].

5-Bromo-3-ethyloxindole

A solution of 3-ethyloxindole (6.0 g, 40 mmol) and sodium acetate (4 g,48 mmol) in acetic acid (100 ml) was treated with bromine (6.4 g, 40mmol). After 30 min. the mixture was diluted with water and extractedwith EtOAc (2×); the combined organic layers were washed with water,sat. sodium hydrogen carbonate solution, and brine, dried (MgSO₄) andevaporated to afford the crude product (9.2 g, 96%). A sample wasrecrystallized from EtOAc/hexane to obtain the subtitled compound, m.p.130-132° C.; ¹H-NMR (DMSO-d₆) δ 0.74 (t, 3H, J=7.5 Hz), 1.8-2.0 (m, 2H),3.45 (t, 1H, J=5.5 Hz,), 6.76 (d, 1H, J=8.35 Hz), 7.42 (m, 1H), 10.43(s, 1H); MS (−ESI) m/z 238/240 (M−H).

A solution of 5-bromo-3-ethyl-oxindole (3.5 g, 14.6 mmol),3-chlorophenylboronic acid (2.4 g, 15 mmol), potassium carbonate (4.5 g,33 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.87 g, 0.75mmol) in dimethoxyethane (160 ml), ethanol (40 ml), and water (40 ml)was heated to reflux to 6 hours. After cooling to RT, the mixture wasdiluted with water and extracted with EtOAc (3×). The combined organicextracts were washed with water, then brine, dried (MgSO₄) andevaporated. The residue was purified by column chromatography (SiO₂,EtOAc:hexane 1:3) to afford the title compound (0.46 g, 12%), m.p.118-120° C.; ¹H-NMR (DMSO-d₆) δ 0.78 (t, 3H, J=7.25 Hz) 1.8-2.02 (m,2H), 3.47 (t, 1H, J=5.71 Hz), 6.89 (d, 3H, J=8.1 Hz), 7.35 (m, 1H), 7.44(t, 1H, J=7.91 Hz), 7.51 (m, 1H), 7.58 (m, 2H), 7.67 (t, 1H, J=1.76 Hz),10.5 (s, 1H); MS (−ESI) m/z 270 (M−H).

Example 7 5-(3-Chloro-phenyl)-3,3-diethyl-1,3-dihydro-indol-2-one

A solution of 3-ethylindol-2-one (16 g, 0.1 mol) in dry THF (200 ml)under N₂ was cooled to −25° C. and treated drop wise with n-butyllithium(2.5M in hexanes, 80 ml, 0.2 mol). To the resulting solution was addedN,N,N′,N′-tetramethylethylenediamine (30 ml, 0.2 mol). After 30 min.iodoethane (8 ml, 0.1 mol) was added and the reaction mixture wasallowed to warm to RT and stirred over night. The reaction mixture waspoured into an aqueous NH₄Cl solution, extracted with EtOAc (2×) and thecombined organic layers were washed with dil. HCl, water, brine, dried(MgSO₄) and concentrated. The residual oil was triturated with hexane toafford the title product (9 g, 45%), m.p. 156-159° C.; ¹H NMR (DMSO-d₆)δ 10.44 (s, 1H), 7.70-7.69 (t, 1H), 7.62-7.59 (m, 1H), 7.58 (d, 1H,J=1.7 Hz), 7.53-7.50 (m, 1H), 7.45-7.41 (t, 1H), 7.36-7.35 (m, 1H),7.34-7.33 (m, 1H), 6.91-6.89 (d, 1H J=8.2 Hz), 1.87-1.80 (m, 2H),1.77-1.70 (m, 2H), 0.54-0.50 (t, 6H); MS (+ESI) m/z 190 (M+H).

5-Bromo-1,3-dihydro-3,3-diethyl-[2H]-indol-2-one

A solution of 3,3-diethylindol-2-one (8 g, 40 mmol) and sodium acetate(4 g, 48 mmol) in acetic acid (100 ml) was treated with bromine (6.4 g,40 mmol). After 30 min. the mixture was diluted with water and extractedwith EtOAc (2×); the combined organic layers were washed with water,sat. sodium hydrogen carbonate solution, then brine, dried (MgSO₄) andevaporated to afford the crude product (7.6 g, 75%). A sample wasrecrystallized from EtOAc/hexane to obtain the subtitled compound, m. p.164-165° C.; ¹H-NMR (DMSO-d₆) δ 10.45 (s, 1H), 7.41-7.40 (d, 1H, J=2.2Hz), 7.34-7.31 (m, 1H), 6.78-6.76 (d, 1H J=8.2 Hz), 1.78-1.65 (m, 4H),0.50-0.46 (m, 6H); MS (−ESI) m/z 266/268 (M−H).

A solution of 5-bromo-1,3-dihydro-3,3-diethyl-[2H]-indol-2-one (2.7 g,10 mmol), 3-chlorophenylboronic acid (1.6 g, 10 mmol), potassiumcarbonate (4 g, 30 mmol) and tetrakis(triphenylphosphine)palladium(0)(0.5 g, 0.4 mmol) in dimethoxyethane (100 ml), ethanol (25 ml), andwater (25 ml) was heated to reflux for 6 hours. After cooling to RT, themixture was diluted with water and extracted with EtOAc (2×). Thecombined organic extracts were washed with water, then brine, dried(MgSO₄) and evaporated. The residue was purified by columnchromatography (SiO₂, EtOAc:hexane 1:3) to afford the title compound(0.8 g, 27%), m.p. 195-197° C.; ¹H-NMR (DMSO-d₆) δ 7.70 (t, 1H, J=2 Hz),7.62-7.60 (m, 1H), 7.58 (d, 1H, J=1.7 Hz), 7.52, (dd, 1H, J=8.1, 2 Hz),7.43 (t, 1H, J=7.9 Hz), 7.36-7.33 (m, 1H), 6.90 (d, 1H, J=8.1 Hz),1.87-1.70 (m, 4H) and 0.52 (t, 6H, J=7.4 Hz); MS (+APCI) m/z 300/302(M−H).

Example 8 5-(3-Chloro-phenyl)-3-methoxy-3-methyl-1,3-dihydro-indol-2-one

A solution of 5-bromoisatin (5.0 g, 22 mmol) in dry THF (50 cm³) underN₂ was cooled to 0° C. and treated drop-wise with methyl magnesiumbromide (3M in diethylether, 14.7 cm³, 44 mmol) and the mixture wasallowed to warm up-to room temperature. The reaction was poured intosat. ammonium chloride solution, then extracted into EtOAc (×3). Thecombined organic layers were then washed with water, brine, dried(MgSO₄) and evaporated. The residue was then purified by columnchromatography (SiO₂, EtOAc:hexane, gradient elution) to afford5-bromo-3-hydroxy-3-methyl-1,3-dihydro-indol-2-one (1.53 g, 6.32 mmol,29%): ¹H NMR (DMSO-d₆) δ 1.38 (s, 3H), 5.99 (s, 1H), 6.77 (d, 1H, J=1.7Hz), 7.38 (s, 1H, br); MS ((−) ESI) m/z 240/242 (M)⁻.

5-bromo-3-hydroxy-3-methyl-1,3-dihydro-indol-2-one (1.0 g, 4.1 mmol) wasdissolved in dry DMF (15 cm³) cooled to 0° C. and treated with potassiumtert-butoxide (1M in THF, 4.5 cm³, 4.5 mmol). After 15 min.methyl-p-toluenesulfonate (0.93 g, 5 mmol) was added and the mixture wasallowed to warm up-to room temperature. After 2 h the mixture was pouredinto saturated ammonium chloride solution and extracted with EtOAc (×2),then the combined organic layers were washed with water, sodiumhydroxide (1N, ×2), water (×3), dried (MgSO₄) and evaporated. Theresidue was then purified by column chromatography (SiO₂, EtOAc:hexane,gradient elution) to afford5-bromo-3-methoxy-3-methyl-1,3-dihydro-indol-2-one (0.56 g, 2.2 mmol,53%): ¹H NMR (CDCl₃) δ 1.59 (s, 3H), 3.18 (s, 3H), 6.73 (d, 1H, J=8.2Hz), 7.45 (dd, 1H, J=8.2, 2 Hz), 7.52 (d, 1H, J=2 Hz); MS (EI) m/z 225(M)⁺.

A solution of 5-bromo-3-methoxy-3-methyl-1,3-dihydro-indol-2-one (0.52g, 2.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.1mmol) was dissolved in dimethoxyethane (22 cm³). After 15 min.,3-chlorophenylboronic acid (0.63 g, 4.1 mmol) and sodium carbonate (1.0g) in water (10 cm³) was added and the reaction was heated under reflux.After 2 h the mixture was cooled, poured into water and extracted withEtOAc (×2), the combined organic extracts were washed with sodiumhydroxide solution (1N, ×2) water, brine, dried (MgSO₄) and evaporated.The residue was then purified by column chromatography (SiO₂,EtOAc:hexane, 5:1) to afford5-(3-chloro-phenyl)-3-methoxy-3-methyl-1,3-dihydro-indol-2-one (0.17 g,0.58 mmol, 29%): ¹H NMR (CDCl₃) δ 1.65 (s, 3H), 2.91 (s, 1H), 3.24 (s,3H), 6.92 (d, 1H, J=8.1 Hz), 7.26-7.38 (m, 2H), 7.43-7.46 (m, 1H),7.52-7.55 (m, 1H), 7.62 (d, 1H, J=1.8 Hz); MS ((+) APCI) m/z 288 (M+H)⁺.

Example 95-(3-Chloro-phenyl)-3-methoxy-3-prop-1-ynyl-1,3-dihydro-indol-2-one

To a solution of 5-bromoisatin (2.5 g, 11 mmol) in dry THF (100 cm³) at−10° C. under a nitrogen atmosphere was added 1-propynylmagnesiumbromide (0.5 M in THF, 47 cm³, 23.5 mmol). After 1 h, the mixture waspoured into saturated ammonium chloride and extracted with EtOAc (×3),washed with brine, dried (MgSO₄) and evaporated to afford5-bromo-3-hydroxy-3-prop-1-ynyl-1,3-dihydroindol-2-one (2.83 g, 10.6mmol, 97%) which was used without further purification: (CDCl₃) δ 1.83(s, 3H), 6.79 (d, 1H, J=8.0 Hz), 6.90 (s, 1H), 7.41-7.44 (m, 2H), 10.59(s, 1H); MS ((−) ESI) m/z 264 (M−H)⁻.

To a solution of 5-bromo-3-hydroxy-3-prop-1-ynyl-1,3-dihydroindol-2-one(1.0 g, 3.75 mmol) in dry DMF (15 cm³) at 0° C., was added potassiumtert-butoxide (1M in THF, 4.1 cm³, 4.1 mmol). After 15 min. methylp-toluenesulfonate (0.85 g, 4.6 mmol) was added and the mixture wasallowed to warm up to room temperature. After 16 h the mixture waspoured into saturated ammonium chloride, extracted with EtOAc (×3),washed with water, brine, dried (MgSO₄) and evaporated. The residue waspurified by column chromatography (SiO₂, EtOAc:hexane 1:3) to afford5-bromo-3-methoxy-3-prop-1-ynyl-1,3-dihydroindol-2-one (0.62 g, 2.21mmol, 59%): (CDCl₃) δ inter alia 1.87 (s, 3H), 3.19 (s, 3H), 3.35 (s,1H), 6.72 (d, 1H, J=8.3 Hz), 7.48 (dd, 1H, J=8.3, 2 Hz), 7.63 (d, 1H,J=2 Hz): MS (EI) m/z 279 (M)⁺.

5-bromo-3-methoxy-3-prop-1-ynyl-1,3-dihydroindol-2-one (0.56 g, 2.0mmol) and tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.10 mmol)were stirred at room temperature in dimethoxyethane (22 cm³). After 15min. 3-chlorophenylboronic acid (0.63 g, 4.0 mmol) and sodium carbonate(1.06 g, 10 mmol) in water (11 cm³) were added and the mixture heatedunder reflux. After 16 h, the mixture was cooled, poured into water andextracted with EtOAc (×3). The combined organic layers were washed withsodium hydroxide (1N, ×2), brine, dried (MgSO₄) and evaporated. Theresidue was subjected to column chromatography (SiO₂, EtOAc:hexane,gradient elution) and the product triturated with hexane to afford thetitle compound (0.095 g, 0.30 mmol, 15%) as a solid: mp. >190° C.(decomp.); (CDCl₃) δ 1.88 (s, 3H), 3.25 (s, 3H), 3.30 (s, 1H), 6.91 (d,1H, J=8.1 Hz), 7.29-7.39 (m, 2H), 7.44-7.47 (m, 1H), 7.54-7.57 (m, 2H),7.74 (d, 1H, J=1.7 Hz); MS (EI) m/z 311 (M⁺).

Example 10 5-(3-Chloro-phenyl)-1,3-dihydro-indol-2-one

A solution of the 5-bromoxindole (0.5 g, 2.4 mmol) andtetrakis(triphenylphosphine)palladium (0.14 g, 0.12 mmol) indimethoxyethane (10 cm³) was stirred under N₂ for 20 min. To thismixture was then added 3-chlorophenylboronic acid (0.44 g, 2.83 mmol)and sodium carbonate (0.75 g, 7.1 mmol) in water (4 cm³). The solutionwas brought to reflux for 6 h then cooled to RT, poured into water andextracted with EtOAc (×3). The combined organic extracts were washedwith water, brine, dried (MgSO₄), and evaporated. The residue waspurified by column chromatography (SiO₂, ethyl acetate:hexane 1:3) toafford the title compound (0.49 g, 2.0 mmol, 86%) as a tan solid: m.p.169-171° C., ¹H NMR (THF-d₈) δ 3.45 (s, 2H), 6.85 (d, 1H J=8.1 Hz), 7.25(d, J=8.0 Hz, 1H), 7.35 (dd, J=7.8, 7.8 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H),7.49 (d, J=7.8 Hz, 1H), 7.50 (s, 1H), 7.59 (dd, J=1.78, 1.78 Hz, 1H),9.5 (br s, 1H); ¹³C NMR (THF-d₈) δ 36.39 (t), 109.80, 123.97, 125.55,127.19 (d), 127.68 (s), 130.89 (d), 133.73, 135.29, 144.23, 145.09,176.45 (s); MS (EI) m/z 243, 245 (M)⁺; Anal. (C₁₄H₁₀ClNO) C, H, N.

Example 115′-(3-Chlorophenyl)spiro[1,3-dioxolane-2,3′-[3H]indol]-2′(1′H)-one5-[3-Chloro-phenyl]-1H-indole-2,3-dione

A solution of 5-(3-Chloro-phenyl)-1,3-dihydro-indol-2-one (10.0 g, 41mmol) in dioxane (200 cm³) and SeO₂ (22.8 g, 205 mmol) was brought toreflux for 2 h then cooled to RT and concentrated onto Florisil. TheFlorisil washed (acetone:CHCl₃ 1:9) and the combined organic extractswere evaporated. The residue was purified by column chromatography(SiO₂, acetone:CHCl₃ 1:8) to afford the subtitled compound (8 g, 31mmol, 76%) as a tan solid: m.p. 256-258° C., ¹H NMR (THF-d₈) δ 6.96 (d,J=8.8 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.4 (dd, J=7.7, 7.7 Hz, 1H), 7.56(d, J=7.7 Hz, 1H), 7.68 (dd, J=1.84, 1.84 Hz, 1H), 7.83-7.86 (m, 2H),10.05 (br s, 1H); ¹³C NMR (DMSO-d₆) δ 113.30 (d), 119.08 (s), 123.44,125.57, 126.65, 127.92, 131.41 (d), 133.88, 134.47 (s), 137.25 (d),141.51, 150.99, 160.15, 184.83 (s); MS (EI) m/z 256 (M−H)⁺; Anal.(C₁₄H₈ClNO₂0.1H₂O) C, H, N.

A solution of the 5-[3-chloro-phenyl]-1H-indole-2,3-dione (0.5 g, 1.9mmol) in toluene (30 cm³) and ethylene glycol (1.1 cm³, 19.4 mmol) andpTsOH (0.04 g, 0.2 mmol) was brought to reflux with azeotropic removalof water for 12 h then cooled to RT. The reaction mixture was dilutedwith EtOAc (100 cm³) and washed with water, sat. sodium hydrogencarbonate solution, brine, dried (MgSO₄), and evaporated to give an oilyresidue. The residue was purified by column chromatography (SiO₂,CH₂Cl₂) to afford the title compound (0.47 g, 1.6 mmol, 80%) as a tansolid: m.p. 159-161° C.; ¹H NMR (DMSO-d₆) δ 4.29-4.39 (M, 4H), 6.93 (d,J=8.6 Hz, 1H), 7.4 (d, J=8.1 Hz, 1H), 7.46 (dd, J=7.9, 7.9 Hz, 1H), 7.7(d, J=7.7 Hz, 1H), 7.68-7.71 (m, 3H), 10.55 (s, 1H); ¹³C NMR (DMSO-d₆) δ65.53 (t), 110.89, 123.25, 124.81 (d), 125.65 (s), 125.83, 126.79,130.09, 130.61 (d), 132.96, 133.64, 141.53, 14267, 174.36 (s); MS (EI)m/z 301/303 (M)⁺; Anal. (C₁₆H₁₂ClNO₃) C, H, N.

Example 125′-(3-Chlorophenyl)spiro[1,3-dioxane-2,3′-[3H]indol]-2′(1′H)-one

The title compound was prepared according to the procedure for example11: m.p. 242-244° C.; ¹H NMR (DMSO-d₆) δ 1.7 (M, 1H), 2.2 (M, 1H), 3.95(m, 2H), 4.78 (t, 2H), 6.9 (d, J=7.9 Hz, 1H), 7.39 (d, J=7.9 Hz, 1H),7.46 (dd, J=7.9, 7.9 Hz, 1H), 7.59-7.68 (m, 3H), 10.59 (br s, 1H); ¹³CNMR (DMSO-d₆) δ 25.19, 60.68 (t), 93.58 (s), 110.94, 122.93, 125.29,126.29, 127.19 (d), 128.65 (s), 129.92, 131.07 (d), 133.16, 134.08,141.61, 142.15, 173.29 (s); MS (EI) m/z 315/317 (M)⁺; Anal.(C₁₇H₁₄ClNO₃) C, H, N.

Example 135′-(3-nitrophenyl)spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-oneSpiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one

To a −25° C. solution of oxindole (2.0 g, 15.0 mmol) in 40 (cm³) ofanhydrous THF under N₂ was added n-butyllithium (1.6 M in hexanes, 19.7cm³, 31.5 mmol) drop-wise. To the resulting milky solution was addedN,N,N′,N′-tetramethylethylenediamine (4.75 cm³, 31.5 mmol). After 30min. a solution of 1,4-diiodobutane (21.9 g, 70.6 mmol) in THF (3 cm³)was added and the reaction mixture was allowed to warm to RT and stirredfor 14 h. The reaction mixture was poured into water, extracted withEtOAc (×2), then the combined organic layers were washed with dil. HCl(pH 1), water (×2), dried (MgSO₄) and evaporated. The residue waspurified by column chromatography (SiO₂, EtOAc:hexane 1:4) to afford thesubtitled compound (1.4 g, 7.5 mmol, 50%) as a tan solid: ¹H NMR (CDCl₃)δ 1.8-2.2 (m, 8H), 6.94 (dd, J=7.5, 1.0 Hz, 1H), 7.01 (dd, J=7.5, 1.0Hz, 1H), 7.14-7.25 (m, 2H), 9.30 (br s, 1H).

5-Bromo-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one

A solution of spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one (0.27 g,1.4 mmol) and sodium acetate (0.12 g, 1.46 mmol) in acetic acid (10 cm³)was treated with bromine (0.24 g, 1.51 mmol) in acetic acid (2 cm³).After 30 min. the mixture was poured into sat. sodium hydrogen carbonatesolution and extracted with EtOAc (×2), the combined organic layers werewashed with water, sat. sodium hydrogen carbonate solution, water, dried(MgSO₄), and evaporated to give the subtitled compound (0.37 g, 1.47mmol, 96%) as an off-white solid which was used without furtherpurification: ¹H NMR (CDCl₃) δ 1.8-2.27 (m, 8H), 6.79 (d, J=8 Hz, 1H),7.30-7.39 (m, 2H), 8.63 (br s, 1H).

A solution of 5-bromo-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one(0.3 g, 1.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.07 g,0.06 mmol) in dimethoxyethane (8 cm³) was stirred under N₂ for 20 min.To this mixture was then added 3-nitrophenylboronic acid (0.23 g, 1.4mmol) and sodium carbonate (0.36 g, 3.4 mmol) in water (3 cm³). Thesolution was brought to reflux for 3 h then cooled to RT, poured intowater and extracted with EtOAc (×3). The combined organic extracts werewashed with water, brine, dried (MgSO₄), and evaporated. The residue waspurified by column chromatography (SiO₂, ethyl acetate:hexane 1:3) toafford the title compound (0.21 g, 0.68 mmol, 62%) as a yellow solid:m.p. 238-240° C.; ¹H NMR (DMSO-d₆) δ 1.89-1.99 (m, 8H), 6.96 (d, J=8.1Hz, 1H), 7.58 (dd, J=8.1, 1.8 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H), 7.71 (dd,J=8.0, 8.0 Hz, 1H), 8.13 (dd, J=7.0, 1.0 Hz, 2H), 8.4 (d, J=1.8 Hz, 1H),10.42 (br s, 1H); ¹³C NMR (dioxane-d₈) δ 26.31, 38.13 (t), 53.85 (s),108.9, 121.15, 121.33, 126.23, 129.38, 132.11 (d), 132.6, 138.32,141.84, 142.74, 149.14, 182.68 (s); MS (EI) m/z 308 (M)⁺.

Example 143-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzaldehydeSpiro[cyclohexane-1,3′-[3H]indol]-2′-(1′H)one

A solution of oxindole (25 g, 0.19 mol) in anhydrous tetrahydrofuran(800 cm³) was cooled to −20° C., then n-butyllithium (2.5M in hexanes,152 cm³, 0.38 mol) was added slowly followed byN,N,N′,N′-tetramethylethylenediamine (51 cm³, 0.38 mol,). After 15 min.1,5-diiodopentane (174 g, 0.54 mol) was added slowly and the mixture wasallowed to warm to room temperature. After stirring for 16 h. saturatedaqueous ammonium chloride solution (1 L) and EtOAc (1 L) were added.After 15 min. the layers were separated and the aqueous phase wasextracted EtOAc (×2). The combined organic layers were extracted withhydrochloric acid (1N), then washed with brine (500 cm³), dried (MgSO₄),and concentrated to obtain an oil. The oil was triturated with hexane(200 cm³) and benzene (20 cm³). The precipitate was collected and driedin vacuo to obtain the subtitled compound (26.3 g, 69.6%) as colorlesscrystals: mp 110-114° C.; ¹H NMR (DMSO-d₆) δ 1.67 (m, 10H), 6.84 (d, 1H,J=8 Hz) 6.94 (t, 1H, J=8 Hz), 7.17 (t, 1H, J=8 Hz), 7.44 (d, 1H, J=8Hz), 10.3 (s, 1H).

5′-Bromospiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one

To a solution of spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one (17.6 g,0.09 mol) in acetic acid (300 cm³) was added sodium acetate (8.0 g, 0.1mol) and bromine (14.6 g, 0.091 mol) with stirring. After 30 min. atroom temperature, the reaction mixture was partitioned between water andEtOAc. The aqueous phase was extracted twice with EtOAc. The combinedorganic layers were washed with water, dried (MgSO₄) and evaporated andthe residue was triturated with hexane. The precipitate was collected,and dried in vacuo to obtain the subtitled compound (16.5 g, 67%) asoff-white crystals: mp 196-199° C.; ¹H NMR (DMSO-d₆) δ 1.62 (m, 10H),6.8 (d, 1H, J=6.8 Hz), 7.36 (d, 1H, J=8.2, 1.8 Hz), 7.58 (dd, 1H, J=8.2,1.8 Hz), 10.44 (s, 1H).

To a solution of 5′-bromospiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one(1.00 g, 3.57 mmol) in dimethoxyethane (20 cm³) was addedtetrakis(triphenylphosphine)palladium (0.20 g, 0.17 mmol) undernitrogen. After 15 min. 3-formylphenylboronic acid (1.00 g, 6.93 g) wasadded followed by potassium carbonate (2.90 g, 21 mmol) in water (10cm³). After 20 h at reflux, the mixture was cooled, poured into waterand extracted with EtOAc (×3). The combined organic extract washed withsat. brine, dried (MgSO₄) and evaporated. The residue was purified bycolumn chromatography (SiO₂, EtOAc:hexane, gradient elution) to affordthe title compound (0.66 g, 2.15 mmol, 60%) as a white solid, ¹H NMR(CDCl₃) δ 1.65-1.85 (m, 6H), 1.86-2.08 (m, 4H), 7.22 (d, 1H, J=8 Hz),7.48 (dd, 1H, J=8, 2 Hz), 7.61 (t, 1H, J=8 Hz), 7.66 (d, 1H, J=2 Hz),7.81-7.88 (m, 2H), 8.06 (t, 1H, J=2 Hz), 8.30 (s, 1H, br); MS ((+)ESI)m/z 306 (M+H)⁺.

Example 153-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzaldehydeoxime

To a solution of3-(1′,2′-dihydro-2′-oxospirocyclohexane-1,3′-[3H]indol-5′-yl)benzaldehyde(0.59 g, 1.95 mmol) in EtOH: H₂O (10 cm³, 8:2) was added hydroxylaminehydrochloride (0.17 g, 2.5 mmol) and sodium acetate (0.20 g, 2.5 mmol).After 20 min. the mixture was concentrated, water was added, andextracted with EtOAc (×2). The combined organic layers were washed withsat. sodium hydrogen carbonate solution, water, sat. brine, dried(MgSO₄) and evaporated to afford the title oxime (0.63 g, 1.95 mmol,100%) which was used without further purification, ¹H NMR (CDCl₃) δ1.60-1.84 (m, 6H), 1.85-2.00 (m, 4H), 6.86 (d, 1H, J=8 Hz), 7.36 (dd,1H, J=8, 2 Hz), 7.43-7.50 (m, 1H), 7.57-7.67 (m, 2H), 7.85 (s, 1H, br),8.25 (s, 1H), 8.68 (s, 1H, br), 8.94 (s, 1H, br); MS ((−)ESI) m/z 319(M−H)⁻.

Example 163-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzaldehydemethyloxime ether

To a solution of3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzaldehyde(0.24 g, 0.79 mmol), and sodium acetate (0.083 g, 1.00 mmol) inEtOH:water (5 cm³, 8:2) was added methoxylamine hydrochloride (0.083 g,1.00 mmol). After 30 min. the precipitate was isolated by filtration andwashed with EtOH:water (8:2, ×2), to afford the title compound (0.027 g,0.08 mmol, 10%) as a white solid: mp 198-200 (decomp.) ¹H-NMR: 1.58-2.07(m, 10H), 4.00 (s, 3H), 6.98 (d, 1H, J=8 Hz), 7.42-7.49 (m, 2H),7.53-7.58 (m, 2H), 7.64 (d, 1H, J=2 Hz), 7.75 (s, 1H), 8.07 (s, 1H, br),8.15 (s, 1H); MS ((+)-ESI) m/z 335 (M+H)⁺.

Example 175-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-3-pyridinecarbonitrile

A solution of 3-bromopyridine-5-carbonitrile (2.79 g, 15.26 mmol),hexamethylditin (5.00 g, 15.26 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.20 g, 0.17 mmol) inanhydrous dimethoxyethane (30 cm³) under N₂ was heated under reflux.After 16 h the mixture was concentrated and purified by columnchromatography (SiO₂, EtOAc:hexane 5:95) to afford3-cyanopyridine-5-trimethylstannane (2.82 g, 10.55 mmol, 69%): ¹H NMR(CDCl₃) δ 0.40 (s, 9H), 8.01 (m, 1H), 8.80 (m, 2H); MS ((+) APCI) m/z269 (M+H)⁺.

A solution of 5′-bromospiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one(1.97 g, 7.05 mmol), 3-cyanopyridine-5-trimethylstannane (2.26 g, 8.46mmol), bis(triphenylphosphine)palladium(II)chloride (0.33 g, 0.47 mmol)and lithium chloride (1.48 g, 35 mmol) in anhydrous toluene (30 cm³) washeated under reflux. After 16 h the mixture was cooled, partitionedbetween EtOAc and water, the aqueous layer was re-extracted with EtOAc(×2), the combined organic extracts were washed with water, dried(MgSO₄) and evaporated. The residue was subjected to columnchromatography (SiO₂, EtOAc:hexane, 1:2) and then further purified bypreparative LC (Primesphere C18, 10 micron, 50×250 mm, MeCN:H₂O 1:1, 100cm³/min., RT 7.92 min.) to afford the title compound as white crystals(0.56 g, 1.84 mmol, 26%): mp. 232-234° C., ¹H NMR (CDCl₃) δ 1.68-1.89(m, 6H), 1.93-2.13 (m, 4H), 7.12 (d, 1H, J=8 Hz), 7.49 (dd, 1H, J=8, 2Hz), 7.66 (d, 1H, J=2 Hz), 8.15 (t, 1H, J=2 Hz), 8.39 (s, 1H, br), 8.89(d, 1H, J=2 Hz), 9.06 (d, 1H, J=2 Hz); MS ((+)-ESI) m/z 304 (M+H)⁺.

Example 185′-(Pyrimidin-5-yl)-spiro[cyclohexane-1,3′-[3H]indol]-2′(1H)-one

To a solution of 5′-bromospiro[cyclohexane-1,3′-[3H]indol]-2′-(1′H)-one(11 g, 0.04 mol) in dry tetrahydrofuran (200 cm³) was added sodiumhydride (60% dispersion in mineral oil, 1.6 g, 0.04 mol). After 30 min.stirring at room temperature, the mixture was cooled to −78° C. andbutyl lithium (1.7M in hexanes, 23.2 cm³, 0.04 mol) was added slowly.After 30 min. di-iso-propylborate (25 cm³, 0.11 mol) was added and themixture was allowed to warm to room temperature. After 2 hrs.,hydrochloric acid (1N, 500 cm³) and ethylacetate (500 cm³) were added.The aqueous phase was extracted with ethylacetate, then the combinedorganic layers were washed with water, brine, dried (MgSO₄) andevaporated. The residue was triturated with hexane and the precipitatedried in vacuo to obtain(2′-oxo-2,3-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)boronic acid(8.3 g, 86%) as an off-white solid that was used without furtherpurification. A sample that was further triturated with ethyl acetatehad the following properties: mp. 255-260° C. dec.; ¹H NMR (DMSO-d₆) δ1.50 (m, 2H), 1.73 (m, 8H), 6.82 (d, 1H, J=7.72 Hz) 7.66 (d, 1H, J=7.72Hz) 7.91 (s, 3H, br), 10.36 (s, 1H); MS ((−)ESI) m/z 244 [M−H].

A stirred mixture of 5-bromopyrimidine (3.2 g, 20 mmol) in toluene (20cm³), 2′-oxo-2,3-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′yl)boronicacid (0.49 g, 2.2 mmol) in ethanol (10 cm³), potassium carbonate (0.28g, 2.0 mmol) in water (10 cm³) andtetrakis(triphenylphosphine)palladium(0) (0.15 g, 0.13 mol) was heatedovernight under reflux and in an atmosphere of nitrogen. The reactionmixture was treated with 20 mL of sodium bicarbonate solution and wasthen extracted with ethyl acetate (2×50 mL). The combined organic phaseswere washed with saturated brine, dried (MgSO₄). Recrystallization fromethanol gave 0.13 g of pure product, mp 227-228° C. IR (KBr) 1700 cm⁻¹¹H-NMR (DMSO-d₆) δ 10.48 (s, 1H), 9.13 (s, 1H), 9.11 (s, 2H), 7.86 (s,1H) 7.63 (dd, 1H; J=1.5 Hz and 8.1 Hz), 6.98 (d, 1H J=8.1 Hz), 6.98 (d,1H, J=8.1 Hz) 1.75 (m, 10); MS (ESI) m/z 278 (M−H).

Example 19 5-(3-chlorophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

Prepared according to the procedure for example 14: mp. 164-165° C., ¹HNMR (CDCl₃) δ 1.60-1.78 (m, 6H), 1.81-1.99 (m, 4H), 7.04 (d, J=8.1 Hz,1H), 7.22-7.47 (m, 4H), 7.53 (s, 1H), 7.61 (s, 1H), 9.28 (br s, 1H);¹³C-NMR (CDCl₃) δ 20.17, 24.12, 31.92 (t), 47.22 (s), 109.21, 121.94,124.06, 125.50, 125.79, 125.97, 126.38, 128.96 (d), 132.88, 133.59,135.60, 139.14, 142.17, 182.89 (s); MS (EI) m/z 310, 312 (M−H)⁺.

Example 205′-(3-Chloro-4-fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one

Prepared according to the procedure for example 18: mp 188-189° C.;¹H-NMR (CDCl₃) δ 7.97 (s, 1H), 7.57-7.54 (m, 2H), 7.41-7.34 (m, 2H),7.20 (t, 1H, J=8.7 Hz), 9.96 (d, 1H, J=8.1 Hz), 2.04-1.65 (m, 10H); MS((+)APCI) m/z 330 [M+H]⁺.

Example 215′-(3-Fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one

Prepared according to the procedure for example 18: mp 171-172° C.;¹H-NMR (CDCl₃) δ 8.43 (s, 1H), 7.62 (d, 1H, J=1.8 Hz), 7.42 (dt, 1H,J=6.2, 2.0 Hz), 7.39-7.37 (m, 1H), 7.33 (dt, 1H, J=5.1, 1.3 Hz), 7.26(dq, 1H, J=5.9, 2.1 Hz), 7.05-6.99 (m, 2H), 2.03-1.64 (m, 10H); MS((+)APCI) m/z 296 [M+H]⁺.

Example 225′-(3,5-Difluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one

Prepared according to the procedure for example 18: mp 180-183° C.;¹H-NMR (CDCl₃) δ 8.35 (s, 1H), 7.59 (d, 1H, J=2.0 Hz), 7.40 (dd, 1H,J=6.2, 2.0 Hz), 7.10-7.03 (m, 2H), 6.99 (d, 1H, J=8.1 Hz), 7.76 (tt, 1H,J=4.3, 2.3 Hz), 2.05-1.62 (m, 10H); MS ((+)APCI) m/z 314 [M+H]⁺.

Example 235-(3,4-Difluorophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

Prepared according to the procedure for example 14: m.p. 187-189° C.;¹H-NMR (DMSO-d₆) δ 1.5-2.0 (m, 10H), 6.9 (d, J=8.13 Hz, 1H), 7.40-7.51(m, 3H), 7.66-7.76 (m, 2H), 10.4 (s, 1H); MS (−ESI) m/z 312 (M−H)⁻.

Example 245-[3-(Methylthio)phenyl]spiro[cyclo-hexane-1,3-[3H]indol]-2(1H)-one

Prepared according to the procedure for example 18: ¹H NMR (CDCl₃) δ1.62-2.06 (m, 10H), 2.54 (s, 3H), 6.96 (d, J=8.0 Hz, 1H), 7.2-7.5 (m,5H), 7.62 (s, 1H), 7.75 (s, 1H); ¹³C NMR (DMSO-d₆) δ 16.37 (q), 21.62,25.58, 33.37 (t), 48.67 (s), 110.55, 123.56, 124.36, 125.68, 126.94,129.64 (d), 135.31, 136.91, 139.33, 140.27, 142.49, 184.29 (s); MS (EI)m/z 324 (M+H)⁺.

Example 255′-[3-(Methysulfinylphenyl]spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one

A solution of5-[3-(Methylthio)phenyl]spiro[cyclo-hexane-1,3-[3H]indol]-2(1H)-one(0.15 g, 0.46 mmol) in methanol (6 cm³) was treated with NaIO₄ (0.11 g,0.51 mmol). The reaction was allowed to stir at RT overnight. Themethanol was evaporated and the residue taken up in EtOAc (50 cm³) andH₂O. The EtOAc layer washed with brine, dried (MgSO₄), and evaporated.The residue was purified by column chromatography (SiO₂,CH₂Cl₂:methanol, 8:2) to afford the title compound (0.11 g, 0.32 mmol,70%) as a white solid: m.p. 190-191° C. ¹H NMR (CDCl₃) δ 1.65-2.05 (m,10H), 2.80 (s, 3H), 7.02 (dd, J=8.0, 3.1 Hz, 1H), 7.46 (d, J=8.0 Hz,1H), 7.52-7.75 (m, 4H), 7.0 (s, 1H), 8.7 (s, 1H); ¹³C NMR (DMSO-d₆) δ21.59, 25.54, 33.44 (t), 44.38 (q), 48.46 (s), 110.53, 12.05, 123.31,127.08, 129.94, 130.15 (d), 134.17, 137.2, 140.73, 143.27, 146.61,183.71 (s); MS (EI) m/z 339 (M)⁺.

Example 265-[3-(Methysulfonyl)phenyl]spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

A solution of the5-[3-(Methylthio)phenyl]spiro[cyclo-hexane-1,3-[3H]-indol]-2(1H)-one(0.15 g, 0.46 mmol) in CH₂Cl₂ (2 cm³) was added to a solution of mCPBA(0.4 g, 2.3 mmol) in CH₂Cl₂ (5 cm³) at RT. The reaction was allowed tostir overnight. The mixture was diluted with CH₂Cl₂ (50 cm³) and washedwith saturated bicarbonate solution, water, brine, dried (MgSO₄), andevaporated. The residue was crystallized (Hexane-EtOAc) to afford thetitle compound (0.132 g, 0.8 mmol, 80%) as an off white solid: m.p. 240°C.; ¹H NMR (CDCl₃) δ 1.55-2.1 (m, 10H), 3.15 (s, 3H), 7.01 (d, J=8.1 Hz,1H), 7.47 (dd, J=8.1, 1.5 Hz, 1H), 7.6-7.7 (m, 2H), 7.82-7.97 (m, 3H),8.12 (s, 1H); ¹³C NMR (DMSO-d₆) δ 21.54, 25.50, 33.45 (t), 44.97 (q),48.44 (s), 110.60, 123.28, 125.92, 127.20, 128.52, 130.31 (d), 132.46,133.65, 137.34, 140.70, 141.53, 143.25, 183.63 (s); MS (EI) m/z 356(M+H)⁺.

Example 275′-(3-Chloro-5-fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one

Prepared according to the procedure for example 18: mp 178-180° C.;¹H-NMR (CDCl₃) δ 8.50 (s, 1H), 7.57 (d, 1H, J=1.8 Hz), 7.39 (dd, 1H,J=6.2, 1.9 Hz), 7.33-7.32 (m, 1H), 7.15 (dq, 1H, J=5.7, 1.7, 0.7 Hz),7.06 (dq, 1H, J=4.2, 1.9, 0.4 Hz), 7.00 (d, 1H, J=8.1 Hz), 2.05-1.64 (m,10H); MS ((−)ESI) [M−H]⁻ @ (m/z 328.

Example 285-(3-Bromo-5-fluorophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

Prepared according to the procedure for example 18: mp. 194-196° C.; ¹HNMR (CDCl₃) δ 1.66-2.04 (m, 10H), 7.00 (d, 1H, J=8.0 Hz), 7.17-7.28 (m,2H), 7.41 (dd, 1H, J=8, 1.8 Hz), 7.49 (t, 1H, J=1.4 Hz), 7.58 (d, 1H,J=1.5 Hz) and 8.24 (s, 1H, br); MS ((+)−EI) m/z 373/375 [M⁺].

Example 295′-(3-Fluoro-5-methylphenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one

A solution of 3-fluoro-5-methoxybenzene trifluoromethanesulfonate (1.6g, 5.8 mmol) and tetrakis-(triphenylphosphene)-palladium(0) (0.33 g, 286mmol) in dimethoxyethane (50 mL) was stirred under N₂ for 20 minutes. Tothis mixture was then added lithium bromide (1.5 g, 172 mmol). Thissolution was stirred under N₂ for 10 minutes. To this mixture was thenadded (2′-oxo-2,3-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)boronicacid (1.3 g, 5.7 mmol) and sodium carbonate (1.2 g, 11.5 mmol) indistilled water (5 mL). The solution was brought to reflux for 6 hours,cooled to room temperature, poured into distilled water and extractedwith EtOAc (×3). The combined organic extracts were washed with 2N NaOH,water, brine, dried (MgSO₄), and evaporated. The residue was purified bycolumn chromatography (SiO₂, EtOAc:Hexane 2:5) to afford the titlecompound (0.6 g, 32%) as an off-white solid: mp 180-182° C.; ¹H-NMR(CDCl₃) δ 8.21 (s, 1H), 7.60 (d, 1H, J=1.8 Hz), 7.41 (dd, 1H, J=6.2, 1.9Hz), 6.97 (d, 1H, J=7.9 Hz), 6.88-6.86 (m, 1H), 6.84 (t, 1H, J=1.8 Hz),6.59 (dt, 1H, J=6.2, 2.2 Hz), 3.86 (s, 3H), 2.00-1.62 (m, 10H); MS((−ESI) [M−H]⁻ @ (m/z 324.

Example 305′-(3-Nitrophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one

Prepared according to the procedure for example 14: mp. 196-198° C., ¹HNMR (CDCl₃) δ 1.67-1.81 (m, 6H), 1.82-2.05 (m, 4H), 7.04 (d, 1H, J=8Hz), 7.48 (dd, 1H, J=8 and 1 Hz), 7.59 (d, 1H, J=8 Hz), 7.63-7.65 (m,1H), 7.87-7.90 (m, 1H), 8.16-8.20 (m, 1H), 8.38 (s, br, 1H), 8.41 (t,1H, J=2 Hz); MS ((−)ESI) m/z 321 (M−H)⁻.

Example 313-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)aniline

A solution of5′-(3-Nitrophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one (3.6 g,11 mmol) in methanol (150 ml) was shaken with 10% palladium on charcoal(1 g) under a hydrogen atmosphere at 40 psi. The catalyst was filteredoff and the solution was concentrated to obtain a residue. The residuewas dissolved in ether and ethanolic hydrochloric acid was added. Thesolid thus obtained was recrystallized from methanol/ether to obtain thetitle compound (1.7 g, 47%): m.p. 275-278° C.; ¹H-NMR (DMSO-d₆) δ1.5-2.0 (m, 110H), 6.98 (d, J=8.05 Hz, 1H), 7.26 (d, J=7.90 Hz, 1H),7.45-7.62 (m, 4H), 7.67 (d, J=8.3 Hz, 1H), 9.0-11.0 (s, 2H, br), 10.5(s, 1H), MS ((+)APCI) m/z 293 (M+H).

Example 325-(3-Fluoro-5-nitrophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

Prepared according to the procedure for example 18: mp. 191-193° C.; ¹HNMR (CDCl₃) δ 1.66-2.07 (m, 10H), 7.07 (d, 1H, J=8 Hz), 7.49 (dd, 1H,J=8, 1.8 Hz), 7.59-7.64 (m, 2H), 7.89 (dt, 1H, J=8.1, 2.1 Hz), 8.25 (s,1H) and 8.54 (s, 1H); MS ((+)-APCI) m/z 341 [M+H]⁺.

Example 335′-(3-Hydroxyphenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one

Prepared according to the procedure for example 18: mp. 213-216° C.; ¹HNMR (CDCl₃) δ 1.60-1.96 (m, 10H), 6.78-6.82 (m, 1H), 6.94 (d, 1H, J=8Hz), 7.01-7.04 (m, 2H), 7.23 (t, 1H, J=7.7 Hz), 7.38 (d, 1H, J=8 Hz),7.61 (s, 1H), 8.91 (s, 1H) and 9.73 (s, 1H, br); MS ((+)-APCI) m/z 294[M+H]⁺.

Example 344-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-thiophenecarbonitrile3-(Trimethylstannyl)-2-thiophenecarbonitrile

A solution of 3-bromo-2-thiophenecarbonitrile (0.8 g, 4.3 mmol),tetrakis(triphenylphosphine)palladium(0) (0.25 g, 0.2 mmol) andhexamethylditin (1.4 g, 4.3 mmol) in dimethoxyethane (5 cm³) was heatedunder reflux for 14 hours then cooled to room temperature. The reactionmixture was absorbed onto florisil and purified by column chromatography(SiO₂, methylene chloride:hexane 1:9) to afford the title compound (1.04g, 3.8 mmol, 90%) as a clear viscous oil: ¹H NMR (CDCl₃) δ 0.35 (s, 9H),7.56 (d, J=0.9 Hz, 1H), 7.66 (d, J=0.9 Hz, 1H).

A solution of the 5′-bromospiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one(0.53 g, 1.9 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.1 g,0.14 mmol) and triphenylarsine (0.14 g, 0.47 mmol) in dimethoxyethane (8cm³) was stirred under N₂ for 20 min. To this mixture was then added3-(trimethylstannyl)-2-thiophenecarbonitrile (0.64 g, 2.35 mmol). Thesolution was brought to reflux for 32 h. After cooling to roomtemperature the reaction mixture was absorbed onto florisil and purifiedby column chromatography (SiO₂, ethyl acetate:hexane 2:3) to afford thetitle compound (0.43 g, 1.39 mmol, 74%) as an off white solid: ¹H NMR(CDCl₃) δ 1.56-2.1 (m, 10H), 6.97 (d, J=8.0 Hz, 1H), 7.39 (dd, J=8.03,1.45 Hz, 1H), 7.57 (d, J=1.45 Hz, 1H), 7.59 (d, J=1.4 Hz, 1H), 7.84 (d,J=1.4 Hz, 1H), 8.32 (br s, 1H); ¹³C-NMR (CDCl₃) δ 22.07, 26.56, 34.4(t), 48.13 (s), 110.18 (d), 111.3, 114.75 (s), 122.92, 126.76 (d),128.44 (s), 137.55 (d), 138.11, 142.71, 144.49, 182.13 (s); MS (EI) m/z307 (M−H)⁺.

Example 355-(2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′yl-2-thiophenecarbonitrile5-Bromo-2-thiophenecarbonitrile

A mixture of 5-bromo-2-thiophenecarboxaldehyde (96.0 g, 500 mmol),hydroxylamine hydrochloride (111.9 g, 500 mmol), pyridine (500 mL), andethanol (500 mL) was heated under nitrogen at reflux for two hours. Thereaction mixture was cooled to ambient temperature and concentrated invacuo to give an oil. The crude product was triturated twice with icewater and the solid obtained was collected on a filter. A mixture of aportion of the above solid (44.31 g, 215 mmol), copper(II)acetatemonohydrate (4.2 g, 21 mmol) in acetonitrile (1.4 L) was heated atreflux for three hours. The solvent was removed in vacuo and the residuewas dissolved in ethyl acetate. The solution washed with 5% aqueoussulfuric acid (2×30 mL), water (2×30 mL), brine (20 mL), and dried(MgSO₄). The solvent was removed in vacuo and the residue was dissolvedin a minimum amount of chloroform (1 L) and allowed to crystallize. Thecrystal obtained was collected on a filter and the filtrate wasconcentrated and purified by a chromatography (silica gel, chloroform)to give the subtitled compound as an off-white solid (31.5 g combined,58%): IR (film) cm⁻¹ 2200; ¹H-NMR (CDCl₃) δ 7.39-7.38 (d, 1H, J=4.1 Hz),7.10 (d, 1H, J=4.0 Hz); MS (EI) m/z 187 (M⁺, 98%) 189 (M⁺, 100%).

The title compound was prepared according to the procedure for example18 using 5-bromo-2-thiophenecarbonitrile and(2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)boronicacid: mp. 225-228° C.; ¹H NMR (DMSO-d₆) δ 1.63 (m, 8H), 1.90 (m, 2H)6.91 (d, 1H, J=8.13 Hz), 7.55 (dd, 1H, J=8.13, 1.76 Hz), 7.60 (d, 1H,J=4.17 Hz), 7.75 (d, 1H, J=1.76 Hz), 7.93 (d, 1H, J=4.17 Hz), 10.51 (s,1H); MS ((+)APCI) m/z 309 [M+H]⁺.

Example 364-Methyl-5-(2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-2-thiophenecarbonitrile

Prepared according to the procedure for example 18: m.p. 200-203° C.; ¹HNMR (DMSO-d₆) δ 1.63 (m, 8H), 1.87 (m, 2H), 2.27 (s, 3H), 6.95 (d, 1H,J=8.13 Hz), 7.34 (dd, 1H, J=8.13, 1.98 Hz) 7.54 (d, 1H, J=1.98 Hz), 7.82(s, 1H) 10.50 (s, 1H); MS ((+)APCI) m/z 323 [M+H]⁺.

Example 374-Ethyl-5-(2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-2-thiophenecarbonitrile

Prepared according to the procedure for example 18: mp 214-217° C. ¹HNMR (DMSO-d₆) δ 10.55 (s, 1H), 7.95 (s, 1H), 7.51 (s, 1H), 7.33-7.30 (m,1H), 6.98-6.96 (d, 2H J=8.0 Hz), 2.67-2.62 (m, 2H), 1.89-1.86 (m, 2H),1.69-1.55 (m, 8H), 1.20-1.15 (t, 3H); MS ((+)APCI) m/z 337 [M+H]⁺. Anal.Calc. For C₂₀H₂₀N₂OS.½H₂O: C, 69.54; H, 6.13; N, 8.11. Found: C, 69.51;H, 6.06; N, 7.57.

Example 385-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-thiophene-3-carbonitrile

Prepared according to the procedure for example 18: m.p. 188-190° C.;¹H-NMR (DMSO-d₆) δ 1.5-2.0 (m, 10H), 6.89 (d, J=7.91 Hz, 1H), 7.49 (dd,J=7.91, 1.98 Hz, 1H), 7.75 (d, J=1.76 Hz, 1H), 7.86 (d, J=1.32 Hz, 1H),8.44 (d, J=1.32 Hz, 1H); MS (−ESI) m/z 307 (M−H).

Example 392-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-thiophene-2-carbonitrile

Prepared according to the procedure for example 18: m.p. 207-9° C.;¹H-NMR (DMSO-d₆) δ 1.4-2.0 (m, 10H), 7.0 (d, J=8.13 Hz, 1H), 7.48 (d,J=5.27 Hz, 1H), 7.54 (dd, J=8.13 Hz, 1.98 Hz, 1H), 7.71 (d, J=5.49 Hz,1H), 7.85 (d, J=1.76 Hz, 1H), 10.6 (s, 1H); MS (−ESI) m/z 307 (M−H).

Example 405-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-3-furancarbonitrile

Prepared according to the procedure for example 18: m.p. 243-245° C.¹H-NMR (DMSO-d₆) δ 10.48 (s, 1H), 8.62 (d, 1H J=0.7 Hz), 7.76 (d, 1HJ=1.5 Hz), 7.58-7.55 (dd, 1H), 7.33 (d, 1H J=0.7 Hz), 6.92-6.90 (d, 1HJ=8.1 Hz), 1.87-1.83 (m, 2H), 1.73-1.53 (m, 8H). MS ((+)EI) m/z 292(M⁺).

Example 415-(5-Chloro-2-thienyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

Prepared according to the procedure for example 18: m.p. 191-192° C.; ¹HNMR (CDCl₃) δ 1.6-2.1 (m, 10H), 6.85-6.95 (m, 2H), 6.98 (d, J=4.0 Hz,1H), 7.36 (dd, J=7.5, 1.6 Hz, 1H), 7.53 (d, J=0.9 Hz, 1H), 7.80 (br s,1H); ¹³C-NMR (THF-d₈) δ 21.35, 25.33, 33.12 (t), 48.32 (s), 110.40,121.66, 121.96, 125.44, 127.25 (d), 128.17, 128.43, 136.92, 140.20,143.43, 183.72 (s); MS (EI) m/z 318 (M+H)⁺.

Example 425-(5-Acetyl-2-thienyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

Prepared according to the procedure for example 18: m.p. 195-196° C., ¹HNMR (CDCl₃) δ 1.6-2.1 (m, 10H), 2.58 (s, 3H), 6.95 (d, J=8.1 Hz, 1H),7.25 (d, J=4.0 Hz, 1H), 7.54 (dd, J=8.1, 1.7 Hz, 1H), 7.66 (d, J=4.0 Hz,1H), 7.7 (d, J=1.7 Hz, 1H), 7.9 (br s, 1H); ¹³C NMR (CDCl₃) δ 22.24,26.19 (t), 27.59 (q), 33.99 (t), 49.02 (s), 111.39, 123.45, 124.12,127.02 (d), 128.59 (s), 134.79 (d), 137.92, 142.23, 143.41, 154.47,184.51, 191.76 (s); MS (EI) m/z 326 (M+H)⁺.

Example 435-(2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′yl)-2-nitro-thiophene

Prepared according to the procedure for example 11: mp. 242° C.(decomp.); ¹H NMR (DMSO-d₆) δ 1.62-1.67 (m, 6H), 1.90-1.99 (m, 2H), 6.94(d, 1H, J=8.1 Hz), 7.64 (d, 1H, J=4.5 Hz), 7.67 (dd, 1H, J=8.2, 1.8 Hz),7.86 (d, 1H, J=1.5 Hz), 8.15 (d, 1H, J=4.5 Hz), 10.62 (s, 1H); MS (EI)m/z 328 (M)⁻.

Example 445′-(5-Nitro-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one2-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester

To a solution of 5′-bromo-spiro[cyclohexane-1,3′-indolin]-2′-one (3.4 g,12 mmol) in 1,2-DME (100 mL) under a nitrogen atmosphere was addedtetrakis(triphenylphospine)palladium(0) (70 mg, 5 mol %). After 15 min,2-borono-1H-pyrrole-1-carboxylic acid, 1-tert butyl ester (1.3 eq, 3.31g, 15.6 mmol) and a solution of K₂CO₃ (2.3 eq, 3.83 g, 27.6 mmol) inwater (5 mL) were added sequentially. The solution was heated to 80° C.for 3 h and allowed to cool. The reaction mixture was poured into water(200 mL) and extracted with EtOAc (2×100 mL). The organic layers werecombined, washed with brine (150 mL) and dried over MgSO₄. The solutionwas filtered, concentrated in vacuo, and the residue was purified byflash column chromatography on silica gel (eluting with 30%EtOAc/hexane) to give subtitled compound: (3.4 g, 76%) as a whitepowder, mp 177° C. ¹H NMR (CDCl₃; 300 MHz) δ 1.38 (s, 9H), 1.59-1.93 (m,10H), 6.18 (m, 1H), 6.23 (‘t’, 1H, J=3 Hz), 6.91 (d, 1H, J=8 Hz), 7.21(d, 1H, J=8 Hz), 7.34 (m, 1H), 7.44 (s, 1H), 8.33 (br s, 1H, D₂Oex). MS((+)-APCI) m/z 367 [(M+H)⁺]. Anal. Calcd for C₂₂H₂₆N₂O₃: C, 72.11; H,7.15; N, 7.64. Found: C, 71.7; H, 7.16; N, 7.5.

2-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-nitro-1H-pyrrole-1-carboxylicacid, tert-butyl carbamates

To a solution of2-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester (72 mg, 0.2 mmol) in MeCN (5 mL) at roomtemperature was added silver nitrate (1.05 eq, 35 mg, 0.2 mmol). After 5min, acetyl chloride (1.0 eq, 15 mg, 0.2 mmol) in MeCN (5 mL) was addedand the solution was allowed to stir for 16 h. Dichloromethane (10 mL)was added, and the solution was filtered through celite and washedsequentially with water, sat. NaHCO₃, water and brine (10 mL of each).The solution was dried over MgSO₄, filtered, and concentrated in vacuo.The residue was purified by flash column chromatography on silica gel(eluting with 40% EtOAc/hexane) to give the subtitled compound (56 mg,70%) as a yellow oil which crystallized from acetone/hexane, mp 163° C.(dec).

2-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-nitro-1H-pyrrole-1-carboxylicacid, tert-butyl ester (0.31 g, 0.85 mmol) was placed in a 5 mL roundbottomed flask stoppered with a rubber septum and equipped with nitrogeninlet and a needle to allow gaseous outflow. A vigorous flow of nitrogenwas maintained as the flask was placed in an oil bath and heated to 200°C. After 5 min at this temperature, the flask was removed from the oilbath and allowed to cool. The black residue washed into a larger flaskwith acetone and adsorbed onto a small amount of silica gel.Purification by flash column chromatography on silica gel (eluting with40% EtOAc/hexane) gave the title carbamate (0.20 g, 85%) as a yellow oilwhich crystallized from acetone/hexane, mp 278° C. (dec). ¹H NMR(DMSO-d₆; 300 MHz) δ 1.55-1.87 (m, 10H), 6.80 (d, 1H, J=4 Hz), 6.91 (d,1H, J=8 Hz), 7.27 (d, 1H, J=4 Hz), 7.77 (dd, 1H, J=8, 1 Hz), 8.04 (d,1H, J=1 Hz), 10.51 (s, 1H), 13.21 (br s, 1H). MS ((+)-APCI) m/z 312[(M+H)⁺]. Anal. Calcd for C₁₇H₁₇N₃O₃: C, 65.58; H, 5.5; N, 13.5. Found:C, 65.57; H, 5.54; N, 13.44.

Example 455′-(5-Nitro-1-methyl-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one5′-(1-Methyl-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one

A mixture of5′-(1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one (0.46g, 1.7 mmol) and potassium carbonate (5 eq, 1.18 g, 8.6 mmol) in DMF (2mL) at room temperature was treated with a solution of iodomethane (3eq, 0.32 g, 5.1 mmol) in DMF (1 mL). The solution was stirred 16 h atroom temperature, then poured into water (10 mL). EtOAc (15 mL) wasadded, the layers were separated, and the aqueous layer was extractedwith EtOAc (2×100 mL). The organic layers were combined, washed withbrine (15 mL) and dried over MgSO₄. The solution was filtered,concentrated in vacuo, and the residue was purified by flash columnchromatography on silica gel (eluting with 40% EtOAc/hexane) to give thesubtitled compound (0.44 g, 76%) as a white powder, mp 148-9° C. ¹H NMR(DMSO-d₆; 400 MHz) δ 1.50-1.62 (m, 3H), 1.62-1.82 (m, 5H), 1.83-1.94 (m,2H), 3.11 (s, 3H), 6.08 (m, 1H), 6.42 (m, 1H), 6.79 (m, 1H), 6.97 (d,1H, J=8.1 Hz), 7.51 (dd, 1H, J=8.1, 1.8 Hz), 7.70 (d, 1H, J=1.7 Hz),11.20 (br s, 1H). Anal. Calcd for C₁₈H₂₀N₂O₁: C, 77.11; H, 7.19; N,9.98. Found: C, 76.44; H, 7.21; N, 9.96.

A mixture of5′-(1-methyl-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one(0.36 g, 1.3 mmol) and silver nitrate (1.1 eq, 0.24 g, 1.4 mmol) inacetonitrile (10 mL) at room temperature was treated with acetylchloride (1.1 eq, 0.1 mL, 1.4 mmol). The mixture was stirred 1 h at thistemperature and then dichloromethane (30 mL) was added and the mixturewas filtered through celite. The organic phase washed sequentially withwater (20 mL), sat. aq. NaHCO₃ (20 mL), and brine (20 mL). The solutionwas dried over MgSO₄, filtered, and concentrated in vacuo. The residuewas purified by flash column chromatography on silica gel (eluting with40% EtOAc/hexane) to give the title compound (21 mg, 5%) as a yellowpowder, mp 210° C. ¹H NMR (DMSO-d₆; 300 MHz) δ 1.55-1.97 (m, 10H), 3.15(s, 3H), 6.77 (dd, 1H, J=4.2, 2.3 Hz), 7.05 (d, 1H, J=8.2 Hz), 7.21 (dd,1H, J=4.2, 2.3 Hz), 7.83 (dd, 1H, J=1.8, 8.2 Hz), 8.0 (d, 1H, J=1.8 Hz),13.0 (br s, 1H). MS ((+)-APCI) m/z 326 [(M+H)⁺]. Anal. Calcd forC₁₈H₁₉N₃O₃: C, 65.45; H, 5.89; N, 12.91. Found: C, 64.66; H, 5.76; N,12.52.

Example 465′-(1H-Indol-4-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one

Prepared according to the procedure for example 18: mp 211-213° C.;¹H-NMR (CDCl₃) δ 8.32 (s, 1H), 7.84 (s, 1H), 7.81 (d, 1H, J=1.8 Hz),7.55 (dd, 1H, J=6.2, 1.8 Hz), 7.40 (dt, 1H, J=6.2, 1.0 Hz), 7.29-7.28(m, 1H), 7.27 (t, 1H, J=3.1 Hz), 7.18 (dd, 1H, J=6.4, 0.9 Hz), 7.00 (dd,1H, J=7.5, 0.4 Hz), 6.72-6.71 (m, 1H), 2.00-1.59 (m, 10H); MS ((+)APCI)[M+H]⁺ (m/z 317.

Example 473-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzonitrile

A solution of3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzaldehydeoxime (0.48 g, 1.49 mmol) in chloroform (10 cm³) was treated withselenium dioxide (0.38 g, 3.50 mmol) and heated under reflux. After 16h, the mixture was concentrated and the residue purified by columnchromatography (SiO₂, EtOAc:hexane 1:4) and the product re-crystallizedfrom EtOAc-hexane to afford the title compound (0.161 g, 0.53 mmol, 35%)as a white solid: mp. 190-191° C.; ¹H NMR (CDCl₃) δ 1.59-1.87 (m, 6H),1.88-2.09 (m, 4H), 7.03 (d, 1H, J=8 Hz), 7.42 (dd, 1H, J=8, 2 Hz), 7.54(t, 1H, J=8 Hz), 7.58-7.65 (m, 2H), 7.78 (dt, 1H, J=7, 2 Hz), 7.83 (m,1H), 8.26 (s, 1H, br); MS ((+) ESI) m/z 303 (M+H)⁺.

Example 483-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-5-fluorobenzonitrile

To a solution of 3,5-dibromofluorobenzene in diethyl ether (100 cm³) at−78° C. was added n-butyl lithium (2.5 M, 8 cm³, 20 mmol) dropwise.After 30 min. the mixture was treated with DMF (20 cm³) in diethyl ether(10 cm³) and stirring was continued at −78° C. After 30 min. the mixturewas quenched with dilute HCl aq., separated and the aqueous layer wasextracted with EtOAc. The combined organic layers were combined, washedwith water, brine, dried (MgSO₄) and evaporated to give3-fluoro-5-bromobenzaldehyde (4.0 g, 19.7 mmol, 100%) as an oil: ¹H NMR(CDCl₃) 6 inter alia 7.50-7.53 (m, 2H), 7.82 (s, 1H) and 9.93 (m, 1H);MS (EI) m/z 202, 204 [M⁺].

To a solution of the last cited compound (4.0 g, 19.7 mmol) inethanol:water (8:2, 50 cm³), was added sodium acetate (1.72 g, 21 mmol)and hydroxylamine hydrochloride (1.45 g, 21 mmol), and the mixture washeated under reflux. After 30 min., the mixture was cooled, evaporatedand the residue partitioned between water and EtOAc. The aqueous layerwas re-extracted with EtOAc and the combined organic layers were washedwith water, saturated sodium hydrogen carbonate solution, brine, dried(MgSO₄) and evaporated to give 3-fluoro-5-bromobenzaldehyde oxime (3.76g, 17.24 mmol, 87%) which was used without further purification: ¹H NMR(CDCl₃) δ 7.24-7.27 (m, 2H), 7.50 (s, 1H), 7.68 (s, 1H) and 8.04 (s,1H); MS (EI) m/z 217 [M⁺].

The above oxime (3.76 g, 17.24 mmol) and copper(II)acetate (370 mg) weredissolved in acetonitrile (100 cm³) under nitrogen and heated underreflux. After 5 h, the mixture was evaporated, the residue taken intoEtOAc, washed with sulfuric acid (1N), water, brine, dried (MgSO₄) andevaporated to give 3-fluoro-5-bromobenzonitrile (3.08 g, 15.39 mmol,89%) which was used without further purification.

The above bromide (3.0 g, 15 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.86 g, 0.75 mmol) weredissolved in dimethoxyethane (130 cm³) under nitrogen. After 15 min.(2′-oxo-2,3-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)boronic acid(2.82 g, 11.5 mmol) and sodium carbonate (3.1 g, 29.3 mmol) dissolved inwater (40 cm³) were added, and the mixture heated under reflux. After 8h the mixture was cooled, poured into water and extracted with EtOAc(×3). The combined organic layers were then washed with water, dried(MgSO₄) and evaporated. The residue was then purified by columnchromatography (EtOAc:hexane, gradient elution), and the productrecrystallized from methanol to give3-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-5-fluorobenzonitrile(1.78 g, 5.55 mmol, 48%): mp 199-205° C.; ¹H NMR (CDCl₃) δ 1.64-2.03 (m,10H), 7.03 (d, 1H, J=8 Hz), 7.31 (dt, 1H, J=7.7 and 1.6 Hz), 7.41 (dd,1H, J=8, 1.7 Hz), 7.49 (dt, 1H, J=9.6, 2 Hz), 7.58 (d, 1H, J=2 Hz), 7.64(s, 1H) and 8.37 (s, 1H): MS (EI) m/z 320 [M⁺].

Example 493-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-fluorobenzonitrile

Prepared according to the procedure for example 18: m.p. 205-206° C. ¹HNMR (DMSO-d₆) δ 10.47 (s, 1H), 8.08-8.06 (dd, 1H), 7.89-7.85 (m, 1H),7.65 (s, 1H), 7.54-7.49 (m, 1H), 7.43-7.40 (tt, 1H), 6.95-6.93 (d, 1HJ=7.9 Hz), 1.97-1.83 (m, 2H), 1.69-1.55 (m, 8H); MS (EI) m/z 320 (M⁺).

Example 50 3-(1′-Diethoxymethyl-1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluorobenzonitrile

A solution of3-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluorobenzonitrile(1.0 eq, 0.27 g, 0.84 mmol) in triethylorthoformate (2 mL, 12 mmol) washeated to 150° C. for 1 h. The reaction mixture was allowed to cool, theexcess triethylorthoformate was removed in vacuo, and the residue waspurified by flash column chromatography on silica gel (eluting with 10%EtOAc/hexane) to give the title compound (0.2 g, 56%) as a white powder,mp 146° C. ¹H NMR (DMSO-d₆; 400 MHz) δ 1.13 (t, 6H, J=7 Hz), 1.60-1.96(m, 10H), 3.48 (m, 2H), 3.66 (m, 2H), 6.17 (s, 1H), 7.35 (d, 1H, J=8.3Hz), 7.68 (dd, 1H, J=2.0, 8.3 Hz), 7.77 (ddd, 1H, J=1.3, 2.4 Hz), 7.89(d, 1H, J=2.0 Hz), 7.92 (dt, 1H, J=2.4, 10.5 Hz), 8.08 (dd, 1H, J=1.3,2.9 Hz). MS ((+)−EI) m/z 422 [M⁺]. Anal. Calcd for C₂₅H₂₇FN₂O₃: C,71.07; H, 6.44; N, 6.63. Found: C, 70.75; H, 6.48; N, 6.52.

Example 513-(7′-Bromo-1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluoro-benzonitrile

A mixture of3-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluorobenzonitrile(0.40 g, 1.23 mmol) and potassium acetate (0.13 g, 1.3 mmol) in glacialacetic acid (3 mL) at room temperature was treated with a solution ofbromine (1.05 eq, 0.21 g, 1.3 mmol) in a glacial acetic acid (3 mL).After stirring for 1 h the mixture was poured onto ice (20 g). Thelayers were separated and the aqueous layer was extracted withdichloromethane (2×10 mL). The organic layers were combined, washedsequentially with 10% aqueous sodium thiosulfate (20 mL), water (2×10mL), saturated sodium bicarbonate (10 mL) and brine (15 mL) and driedover MgSO₄. The solution was filtered, concentrated in vacuo, and theresidue was purified by flash column chromatography on silica gel(eluting with 30% EtOAc/hexane) to give the title compound (0.21 g, 43%)as an oil which crystallized upon addition of 10% EtOAc/hexanes, mp 217°C. ¹H NMR (CDCl₃; 300 MHz) δ 1.56-2.04 (m, 10H), 7.33 (dddd, 1H, J=1.25,2.3, 3.6 and 9.0 Hz), 7.45 (m, 1H), 7.47 (m, 2H), 7.54 (m, 1H), 7.60 (m,1H). MS ((−)-ESI) m/z 399 [M⁻]. Anal. Calcd for C₂₀H₁₆BrFN₂O₁: C, 60.17;H, 4.04; N, 7.02. Found: C, 60.03; H, 4.08; N, 6.83.

Example 523-(7′-Nitro-1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluorobenzonitrile

A mixture of3-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluorobenzonitrile(0.19 g, 0.6 mmol) and silver nitrate 0.11 g, 0.6 mmol) intrifluoroacetic acid (5 mL) was stirred 1 h at room temperature and thenpoured onto ice (20 g). Ether (15 mL) was added, the layers wereseparated, and the aqueous layer was extracted with ether (3×10 mL). Theorganic layers were combined and washed sequentially with water (2×20mL), saturated aqueous NaHCO₃ (20 mL) and brine (15 mL) and dried overMgSO₄. The solution was filtered, concentrated in vacuo, and the residuewas purified by flash column chromatography on silica gel (eluting with20% EtOAc/hexane) to give the title compound (0.2 g, 94%) as a whitepowder, mp 196° C. ¹H NMR (DMSO-d₆; 400 MHz) δ 1.46-1.58 (m, 1H),1.62-1.77 (m, 5H), 1.83 (m, 2H), 1.92-2.20 (m, 2H), 7.85 (dddd, 1H,J=1.3, 2.4, 3.7 and 8.6 Hz), 8.12 (dddd, 1H, J=1.8, 2.4, 4.2 and 10.5Hz), 8.23 (m, 2H), 8.36 (d, 1H, J=2.0 Hz), 11.17 (bs, 1H). MS ((−)-APCI)m/z 365 [M⁻]. Anal. Calcd for C₂₀H₁₆FN₃O₃: C, 65.75; H, 4.41; N, 11.5.Found: C, 65.4; H, 4.54; N, 11.3.

Example 53 3-(7′-Amino-1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluoro-benzonitrile

To a solution of3-(7′-nitro-1′,2′-dihydro-2′-oxospiro-[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluorobenzonitrile(1.0 eq, 0.16 g, 0.4 mmol) in glacial acetic acid (4 mL) at roomtemperature was added a solution of tin(II)chloride dihydrate (0.25 g,1.1 mmol) in hydrochloric acid (2 mL). The yellow mixture was boiled for30 min at which point the yellow color disappeared. After cooling toroom temperature, 1N HCl (10 mL) and ether (20 mL) were added. Thelayers were separated and the aqueous phase was extracted with ether(2×20 mL). The organic layers were combined, washed sequentially withwater (2×20 mL), saturated aqueous NaHCO₃ (20 mL), and brine (20 mL).The solution was dried over MgSO₄, filtered, and concentrated in vacuo.The residue was purified by flash column chromatography on silica gel(eluting with 40% EtOAc/hexane) to give the title compound (70 mg, 50%)as an oil which crystallized upon addition of 10% EtOAc/hexanes, mp241-3° C. ¹H NMR (DMSO-d₆; 400 MHz) δ 1.50-1.75 (m, 8H), 1.82-1.95 (m,2H), 4.98 (s, 2H), 6.90 (d, 1H, J=1.8 Hz), 7.09 (d, 1H, J=1.5 Hz), 7.75(m, 2H), 7.90 (‘s’, 1H), 9.96 (bs, 1H). MS ((+)-APCI) m/z 336 [(M+H)⁺].Anal. Calcd for C₂₀H₁₈FN₃O: C, 71.63; H, 5.41; N, 12.18. Found: C,71.16; H, 5.58; N, 12.18.

Example 545-(3-cyano-4-fluorophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

Prepared according to the procedure for example 18: mp. 239-242° C.; ¹HNMR (CDCl₃) δ 1.64-1.82 (m, 6H), 1.88-2.04 (m, 2H), 7.00 (d, 1H, J=8Hz), 7.29-7.31 (m, 1H), 7.36 (dd, 1H, J=8.8, 2 Hz), 7.54 (d, 1H, J=1.5Hz), 7.73-7.78 (m, 2H) and 8.19 (s, 1H, br); MS ((+)-APCI) m/z 321[M+H]⁺.

Example 555′-(3-Chlorophenyl)spiro[4,4-dimethylcyclohexane-1′,3′-[3H]indol]-2′(1′H)-one

A solution of 3,3-dimethylglutaric anhydride in dry THF (60 cm³) wasadded over 30 min. to lithium aluminum hydride in dry THF (300 cm³)under nitrogen at 0° C. The mixture was then brought gradually up-toreflux. After 3 h, the mixture was cooled, treated with water (3.3 cm³),sodium hydroxide solution (15%, 3.3 cm³) and water (9.9 cm³). Themixture was then filtered, the precipitate extracted with EtOAc (×3),and the combined organics evaporated to afford3,3-dimethyl-1,5-pentanediol (quantitative yield); ¹H NMR (CDCl₃) δ 0.95(s, 6H), 1.57 (t, 4H, J=6.3 Hz), 3.75 (t, 4H, J=6.3 Hz).

A solution of 3,3-dimethyl-1,5-pentanediol (8.4 g, 63.5 mmol) in drypyridine (180 cm³) was cooled to 0° C. under nitrogen and treated over 5h with a solution of p-toluenesulfonyl chloride (26.7 g, 140 mmol) indry pyridine (100 cm³). The mixture was then allowed to warm up to roomtemperature. After 16 h, the mixture was poured into ice/water andextracted with EtOAc (×3). The combined organics were washed with dil.HCl (30%), saturated sodium hydrogen carbonate, brine, dried (MgSO₄) andevaporated to afford 1,5-bis-(3,3-dimethylpentane)-p-toluenesulfonate(19.8 g, 45 mmol) which was used without further purification: ¹H NMR(CDCl₃) 6 inter alia 0.85 (s, 6H), 1.56. (t, 4H, J=7.0 Hz), 2.45 (s,6H), 4.02 (t, 4H, J=7.0 Hz), 7.35 (d, 4H, J=8.0 Hz), 7.77 (d, 4H, J=8.0Hz); MS ((+) APCI) m/z 441 (M+H)⁺.

A solution of 1,5-bis-(3,3-dimethylpentane)-p-toluenesulfonate (53.0 g,120 mmol) and sodium iodide (72.0 g, 480 mmol) was dissolved withstirring in dry acetone (500 cm³). After 16 h at reflux the mixture wascooled, poured into water and extracted with diethylether (×3). Thecombined organic extracts were washed with water, dried (MgSO₄), andevaporated to afford 3,3-dimethyl-1,5-diiodopentane (41.3 g, 117 mmol)as a yellow oil that was used without further purification: ¹H NMR(CDCl₃) 6 inter alia 0.90 (s, 6H), 1.87-1.91 (m, 4H), 3.09-3.15 (m, 4H).

A solution of oxindole (2.0 g, 15 mmol) dissolved in dry THF (50 cm³)under nitrogen was cooled to −60° C. and treated with n-butyllithium(2.5 M in hexanes, 15 cm³, 37.5 mmol) followed byN,N,N′,N′-tetramethylethylenediamine (5.66 g, 37.5 mmol). After 20 min.3,3-dimethyl-1,5-diiodopentane (15.8 g, 45 mmol) in dry THF (10 cm³) wasadded and the mixture was allowed to warm up to room temperature. After16 h, the mixture was poured into water, extracted with EtOAc (×3),washed with water, dilute HCl (10%), water, brine, dried (MgSO₄) andevaporated. The residue was then subjected to column chromatography(SiO₂, EtOAc:hexane, 1:6) to affordspiro[4,4-dimethylcyclohexane-1′,3′-[3H]indol]-2′(1′H)-one (0.37 g, 1.62mmol, 11%): ¹H NMR (CDCl₃) δ 1.08 (s, 3H), 1.10 (s, 3H), 1.23-1.30 (m,2H), 1.54-1.68 (m, 4H), 1.94-2.04 (m, 2H), 6.94 (d, 1H, J=7.7 Hz), 7.01(t, 1H, J=7.6 Hz), 7.20 (t, 1H, J=7.7 Hz), 7.42 (d, 1H, J=7.4 Hz), 8.76(s, 1H, br); MS (EI) m/z 229 (M)⁺.

To a solution of the last cited compound (0.37 g, 1.62 mmol) and sodiumacetate (0.14 g, 1.7 mmol) in acetic acid (5 cm³) was added bromine(0.27 g, 1.7 mmol) in acetic acid (2 cm³). After 30 min. the mixture waspoured into sodium hydroxide solution (2N) and extracted withdichloromethane (×2). The organic extracts were washed with water, dried(MgSO₄) and evaporated to afford5′-bromospiro[4,4-dimethylcyclohexane-1′,3′-[3H]indol]-2′(1′H)-one(0.435 g, 1.41 mmol, 87%) which was used without further purification:¹H NMR (CDCl₃) δ 1.08 (s, 3H), 1.49-1.64 (m, 4H), 1.69-1.74 (m, 2H),1.89-1.98 (m, 2H), 6.77 (d, 1H, J=8.2 Hz), 7.33 (dd, 1H, J=8.2, 1.8 Hz),7.48 (d, 1H, J=1.7 Hz), 7.71 (s, 1H, br); MS ((+)APCI) m/z 308 (M+H)⁺.

The last cited compound (0.56 g, 1.81 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.1 g, 0.08 mmol) weredissolved in dimethoxyethane (20 cm³) under nitrogen. After 20 min.3-chlorophenylboronic acid (0.57 g, 3.64 mmol) and sodium carbonate(0.97 g, 9.15 mmol) were added and the mixture heated under reflux.After 16 h the mixture was cooled, poured into water and extracted withEtOAc (×2). The combined organic layers were washed with sodiumhydroxide (2N), water, brine, dried (MgSO₄) and evaporated. The residuewas then subjected to column chromatography (SiO₂, EtOAc:hexanes, 1:5)to afford the title compound which was triturated with hexane to give asolid (0.26 g, 0.77 mmol, 43%): mp. 184-185° C.; ¹H NMR (CDCl₃) δ 1.11(s, 6H), 1.57-1.80 (m, 6H), 1.45-2.03 (m, 2H), 6.98 (d, 1H, J=8.0 Hz),7.29-7.44 (m, 4H), 5.52-7.55 (m, 2H), 8.12 (s, 1H, br); MS ((+)APCI) m/z340 (M+H)⁺.

Example 565′-(3-Nitrophenyl)spiro[4,4-dimethylcyclohexane-1′,3′-[3H]indol]-2′(1′H)-one

To a solution of5′-bromospiro[4,4-dimethylcyclohexane-1′,3′-[3H]indol]-2′(1′H)-one (0.29g, 0.95 mmol) in dimethoxyethane (15 cm³) was addedtetrakis(triphenylphosphine)palladium(0) (0.053 g, 0.046 mmol). After 20min., 3-nitrophenylboronic acid (0.32 g, 1.9 mmol) and sodium carbonate(0.5 g, 4.75 mmol) in water (7.5 cm³) and the mixture heated underreflux. After 16 h, the mixture was cooled, poured into water andextracted with EtOAc (×2). The combined organic layers were washed withsodium hydroxide solution (2N), water, brine, dried (MgSO₄) andevaporated. The residue was then subjected to column chromatography(SiO₂, EtOAc:hexanes, gradient elution), then the product was trituratedwith hexane to afford the title compound (0.12 g, 0.35 mmol, 37%) as ayellow solid: mp. 230-231° C.; ¹H NMR (CDCl₃) δ 1.18-1.24 (m, 6H),1.57-1.86 (m, 6H), 1.94-2.03 (m, 2H), 7.03 (d, 1H, J=8.0 Hz), 7.48 (d,1H, J=8.0 Hz), 7.59-7.64 (m, 2H), 7.87 (d, 1H, J=7.7 Hz), 8.06 (s, 1H,br), 8.19 (d, 1H, J=7.7 Hz), 8.40 (s, 1H); MS ((+)APCI) m/z 351 (M+H)⁺.

Example 572,3,5,6-Tetrahydro-5-(3-nitrophenyl)spiro[3H-indole-3,4-[4H]pyran]-2(1H)-one

To a solution of sodium iodide (64 g, 0.43 mol) in acetone under N₂ wasadded 2-bromoethyl ether (20 g, 0.086 mol), causing a white solid toprecipitate. After 16 h the mixture was filtered and the filtrateconcentrated. Dichloromethane was added to the residue which wasfiltered, the cake further washed with dichloromethane, the combinedorganic layers were dried (MgSO₄) and evaporated to give 2-iodoethylether (26.61 g, 0.0816 mol, 95%) as a colorless oil: ¹H NMR (CDCl₃) δ3.26 (t, 2H, J=7 Hz), 3.78 (t, 2H, J=7 Hz).

A solution of oxindole (5.00 g, 37.5 mmol) in anhydrous THF under N₂ wascooled to −20° C. n-butyllithium (2.5 M in hexanes, 30 cm³, 75.1 mmol)was added drop-wise followed by N,N,N′,N′-tetramethylethylenediamine(11.4 cm³). After 20 min. a solution of 2-iodoethyl ether (36 g, 112mmol) in anhydrous THF (20 cm³) was added slowly. The mixture wasallowed to warm to room temperature, then after 16 h was brought toreflux. After 5 h the mixture was cooled then poured into water,extracted with EtOAc (×2), the combined organic layers were washed withdil. HCl (pH 1), water (×2), dried (MgSO₄) and evaporated. The residuewas purified by column chromatography (SiO₂, acetone:hexane 1:5) toafford the title compound (0.78 g, 3.82 mmol, 10%) as a white solid: ¹HNMR (CDCl₃) δ 1.84-1.95 (m, 4H), 3.91-3.96 (m, 2H), 4.21-4.27 (m, 2H),6.89-6.92 (m, 1H), 7.06 (t, 1H, J=7, 1 Hz), 7.22 (t, 1H, J=7, 1 Hz),7.35-7.38 (m, 1H).

A solution of the above product (0.78 g, 3.82 mmol) and sodium acetate(0.32 g, 4.02 mmol) in acetic acid (10 cm³) was treated with bromine(0.64 g, 4.02 mmol) in acetic acid (2 cm³). After 30 min. the mixturewas poured into sat. sodium hydrogen carbonate solution and extractedwith EtOAc (×2) washed with water, sat. sodium hydrogen carbonatesolution, water, dried (MgSO₄), and evaporated to give the titlecompound (0.59 g, 2 mmol, 54%) as an off-white solid which was usedwithout further purification: ¹H NMR (CDCl₃) δ 1.83-2.00 (m, 4H),3.91-4.03 (m, 2H), 4.22-4.32 (m, 2H), 6.86 (d, 1H, J=7 Hz), 7.38-7.45(m, 1H), 7.52 (d, 1H, J=1 Hz), 8.36 (s, 1H, br); MS ((+)ESI) m/z 282(M+H)⁺.

A solution of the above product (0.58 g, 2.04 mmol) andtetrakis(triphenylphosphine)palladium (0.11 g, 0.09 mmol) indimethoxyethane (16 cm³) was stirred under N₂ for 20 min. To thismixture was then added 3-nitrophenylboronic acid (0.63 g, 4.06 mmol) andpotassium carbonate (1.68 g) in water (7 cm³). After 3 h at reflux themixture was cooled, poured into water and extracted EtOAc (×3). Thecombined organic extracts were washed with water, brine, dried (MgSO₄)and evaporated. The residue was then subjected to column chromatography(SiO₂, EtOAc:hexane, 1:2) to provide the title compound (0.19 g, 0.58mmol, 28%). A sample which was further purified by preparative LC(Primesphere C18, 10 micron, 50×250 mm, MeCN:H₂O 46:54, 100 cm³/min., RT7.57 min.) had the following properties: mp>250° C., ¹H NMR (acetone-d₆)δ 1.78-1.88 (m, 2H), 1.92-2.01 (m, 2H), 3.85-3.94 (m, 2H), 4.12-4.23(2H), 7.08-7.13 (m, 1H), 7.62-7.69 (m, 1H), 7.70-7.79 (m, 1H), 7.92-7.97(m, 1H), 8.13-8.23 (m, 2H), 8.45-8.51 (m, 1H), 9.55 (s, 1H, br); MS (EI)m/z 341 (M)⁺.

Example 585′-(5-Chloro-3-methylbenzo[b]thien-2-yl)spiro[cyclo-hexane-1,3′-[3H]indol]-2′(1′H)-one

A solution of the 2-bromo-5-chloro-3-methylbenzo[b]-thiophene (0.28 g,1.1 mmol) and tetrakis-(triphenylphosphine) palladium (0.13 g, 0.1 mmol)in dimethoxyethane (8 cm³) was stirred under N₂ for 20 min. To thismixture was then added(2′-oxo-2,3-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)boronic acid(0.32 g, 1.3 mmol) and sodium carbonate (0.35 g, 3.3 mmol) in water (4cm³). The solution was brought to reflux for 12 h then cooled to RT,poured into water and extracted with EtOAc (3×50 cm³). The combinedorganic extracts were washed with water, brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,CH₂Cl₂) to afford the title compound (0.18 g, 0.47 mmol, 45%) as a whitesolid: m.p. 256-258° C., ¹H NMR (DMSO-d₆) δ 1.47-1.97 (m, 10H), 2.42 (s,3H), 6.99 (d, J=8.0 Hz, 1H), 7.39 (d, J=1.6 Hz, 1H), 7.42 (d, J=1.2 Hz,1H), 7.6 (s, 1H), 7.85 (d, J=1.9 Hz, 1H), 7.99 (d, J=8.5 Hz, 1H), 10.53(s, 1H); ¹³C NMR (DMSO-d₆) δ 12.84 (q), 20.96, 25.08, 32.88 (t), 47.23(s), 109.98, 121.99, 124.25, 124.71, 125.01 (d), 126.47, 126.59, 129.17,130.01, 136.51, 140.42, 141.79, 142.76, 181.74 (s); MS (EI) m/z 380(M−H)⁺.

Example 595-(3-Fluoro-4-nitrophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

The title compound was prepared from(2′-oxo-2,3-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)boronic acid(3.2 g, 12.5 mmol) and 4-bromo-2-fluoro-nitrobenzene (3 g, 13.6 mmol) asdescribed for example 18 (0.7 g, 16%) as a yellow solid: mp. 213-215°C.; ¹H NMR (DMSO-d⁶) δ 1.5-1.8 (m, 8H), 1.8-2.0 (m, 2H), 6.96 (d, 1H,J=8.13 Hz), 7.68 (dd, 1H, J=8.13, 1.76 Hz), 7.74 (dd, 1H, J=8.68, 1.76Hz), 7.86 (d, 1H, J=1.98 Hz), 7.92 (dd, 1H, J=13.4, 1.76 Hz), 8.18 (t,1H, J=8.46 Hz) and 10.52 (s, 1H); MS (EI) m/z=340 (M⁺).

Example 604-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-furancarbonitrile

A solution of 3-bromo-5-cyano-furan (0.75 g, 4.4 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.4 g) in ethylene glycoldimethyl ether (20 cm³) was stirred under N₂ for 20 minutes. To thismixture was then added(spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (1.6 g,6.5 mmol) and sodium acetate (1.4 g, 13.1 mmol) in water (5 cm³). Thesolution was brought to reflux for 18 hours and then cooled to roomtemperature, poured into 2N NaOH and extracted with EtOAc (×3). Thecombined extracts were washed with water, brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,EtOAc, hexane) to afford the title compound (0.45 g, 36%) as anoff-white solid. mp: 240-242° C.; ¹H NMR (DMSO-d₆) δ 10.4 (s, 1H), 8.5(s, 1H), 8.2 (s, 1H), 7.7 (s, 1H), 7.5 (dd, 1H, J=1.5 6.5 Hz), 6.9 (d,1H, J=8.0 Hz), 2.0-1.6 (m, 10H); MS (EI) M⁺ @ m/z 292.

Example 615-[4-Fluoro-3-(trifluoromethyl)phenyl]spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

The title compound was prepared from(2′-oxo-2,3-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)boronic acid(2.5 g, 10 mmol) and 5-bromo-2-fluoro-trifluoromethylbenzene (2 g, 8mmol) as described for example 18, to afford the title compound (0.87 g,30%) as a solid: mp. 222° C.; ¹H NMR (DMSO-d₆) δ 1.5-1.8 (m, 8H),1.8-2.0 (m, 2H), 6.92 (d, 1H, J=8.13 Hz), 7.51 (dd, 1H, J=8.13, 1.76Hz), 7.55 (dd, 1H, J=10.54, 9.01 Hz) 7.72 (d, 1H, J=1.76 Hz), 7.90 (dd,1H, J=7.03, 2.20 Hz), 7.98 (m, 1H) and 10.39 (s, 1H); MS (EI) m/z 363(M⁺).

Example 625-[4-Fluoro-3-nitrophenyl]spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

The title compound was prepared from(2′-oxo-2,3-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)boronic acid(2.8 g, 11 mmol) and 5-bromo-2-fluoro-nitrobenzene (2.7 g, 12.2 mmol) asdescribed for example 18, to afford the title compound (2.5 g, 66%) as asolid: mp. 243-245° C.; ¹H NMR (DMSO-d₆) δ 1.8-2.0 (m, 2H), 1.5-1.8 (m,8H), 6.94 (d, 1H, J=8.13 Hz), 7.55 (dd, 1H, J=8.01, 1.87 Hz), 7.63 (dd,J=10.98, 8.79 Hz), 8.07 (m, 1H), 8.30 (dd, 1H, J=7.14, 2.53 Hz) and10.43 (s, 1H); MS (ESI (neg)) m/z 339 (M−H)⁻.

Example 635′-(4-Cyano-3-fluorophenyl)-spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one

A solution of 4-cyano-3-fluoro-bromobenzene (0.76 g, 3.8 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.3 g) in ethylene glycoldimethyl ether (15 cm³) was stirred under N₂ for 20 minutes. To thismixture was then added(spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (1.4 g,5.7 mmol) and sodium acetate (1.2 g, 11.4 mmol) in water (5 cm³). Thesolution was brought to reflux for 18 hours and then cooled to roomtemperature, poured into 2N NaOH and extracted with EtOAc (×3). Thecombined extracts were washed with water, brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,EtOAc, hexane) to afford the title compound (0.45 g, 37%) as anoff-white solid. mp: 258-260° C.; ¹H NMR (DMSO-d₆) δ 8.8 (s, 1H),7.7-7.6 (m, 2H), 7.5 (td, 2H, J=0.9, 1.5, 5.7 Hz), 7.4 (dd, 1H, J=1.5,8.8 Hz), 7.0 (d, 1H, J=8.1 Hz), 2.0-1.6 (m, 10H); MS (−)APCI [M−H⁻] @m/z 319.

Example 642-fluoro-4-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzaldehydeoxime

A solution of 3-fluoro-4-bromobenzaldehyde oxime (0.5 g, 2.2 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycoldimethyl ether (10 cm³) was stirred under N₂ for 20 minutes. To thismixture was then added(spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (0.8 g,3.3 mmol) and sodium acetate (0.7 g, 6.5 mmol) in water (5 cm³). Thesolution was brought to reflux for 18 hours and then cooled to roomtemperature, poured into 2N NaOH and extracted with EtOAc (×3). Thecombined extracts were washed with water, brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,EtOAc, hexane) to afford the title compound (0.25 g, 34%) as anoff-white solid. mp: 240-242° C.; ¹H NMR (DMSO-d₆) δ 11.6 (s, 1H), 10.4(s, 1H), 8.2 (s, 1H), 7.8-7.7 (m, 2H), 7.6-7.5 (m, 3H), 6.9 (d, 1H,J=8.1 Hz), 2.0-1.6 (m, 10H); MS (EI) M⁺ @ m/z 338.

Example 655-(2′-oxo-2′,3′-dihydrospiro[cyclopentane-1,3′-[3H]indol]-5′yl)-2-nitrothiophene

A solution of 2-bromo-5-nitrothiophene (0.6 g, 2.9 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycoldimethyl ether (20 cm³) was stirred under N₂ for 20 minutes. To thismixture was then added(spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (1.0g, 4.3 mmol) and sodium acetate (1.0 g, 10.0 mmol) in water (5 cm³). Thesolution was brought to reflux for 18 hours and then cooled to roomtemperature, poured into 2N NaOH and extracted with EtOAc (×3). Thecombined extracts were washed with water, brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,EtOAc, hexane) to afford the title compound (0.87 g, 96%) as a yellowsolid. mp: 264-266° C.; ¹H NMR (DMSO-d₆) δ 10.6 (s, 1H), 8.1 (d, 1H,J=4.5 Hz), 7.7 (d, 1H, J=1.8 Hz) 7.6 (m, 2H), 6.9 (d, 1H, J=8.1 Hz),2.0-1.9 (m, 8H); MS (EI) M⁺ @ m/z 314.

Example 665-(3-Chloro-4-fluoro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one

A solution of 5-bromo-3,3-dimethyl-1,3-dihydro-indol-2-one (0.35 g, 1.46mmol) and tetrakis(triphenylphosphine) palladium (0.13 g, 0.11 mmol) indimethoxyethane (10 cm³) was stirred under N₂ for 20 min. To thismixture was then added 3-chloro-4-fluorobenzene boronic acid (0.26 g,1.49 mmol) and potassium carbonate (0.62 g, 4.5 mmol) in water (5 cm³).The solution was brought to reflux for 16 h then cooled to RT, pouredinto saturated ammonium chloride and extracted with EtOAc (×3). Thecombined organic extracts were dried (MgSO₄), and evaporated. Theresidue was purified by column chromatography (SiO₂, ethylacetate:hexane 1:3) to afford the title compound (0.124 g, 0.43 mmol,30%) as a white solid: m.p. 206.5-207.8° C., ¹H NMR (DMSO-d₆) δ 1.3 (s,6H), 6.93 (d, J=8.1 Hz, 1H), 7.45 (dd, J=8.9, 8.9 Hz, 1H), 7.5 (dd,J=8.1, 1.8 Hz, 1H), 7.6 (ddd, J=8.9, 7.1, 2.2 Hz, 1H), 7.7 (d, J=1.8 Hz,1H), 7.8 (dd, J=7.1, 2.2 Hz, 1H), 10.5 (s, 1H); MS (EI) m/z 289/291(M)⁺.

Example 67 3-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-benzonitrile(2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl)boronic acid

To a solution of 5′-bromo-3,3-dimethyl-[1,3′-[3H]indol]-2′-(1′H)-one(3.5 g, 14.6 mmol) in dry tetrahydrofuran (60 cm³) was added sodiumhydride (60% dispersion in mineral oil, 0.59 g, 14.6 mmol). After 30min. stirring at room temperature, the mixture was cooled to −78° C. andn-butyl lithium (2.5 M in hexanes, 5.9 cm³, 14.6 mmol) was added slowly.After 30 min. tri-isopropyl borate (9 cm³, 38.9 mmol) was added and themixture was allowed to warm to room temperature. After 8 hrs.,hydrochloric acid (1N, 200 cm³) and ethylacetate (200 cm³) was added andthe mixture stirred for 20 min. The aqueous phase was extracted withethylacetate, then the combined organic layers were washed with water,brine, dried (Na₂SO₄) and evaporated. The residue was triturated withhexane and the precipitate dried in vacuo to obtain(2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl)boronic acid(1.8 g, 8.8 mmol, 60%) as a yellow-white solid that was used withoutfurther purification. ¹H NMR (DMSO-d₆) δ 1.23 (s, 6H), 6.81 (d, J=7.8Hz, 1H) 7.63 (d, J=7.8 Hz, 1H) 7.66 (s, 1H), 7.84 (s, 2H) 8.69 (s, 1H).

A solution of 3-bromobenzonitrile (0.30 g, 1.65 mmol) andtetrakis(triphenylphosphine) palladium (0.13 g, 0.11 mmol) indimethoxyethane (10 cm³) was stirred under N₂ for 20 min. To thismixture was then added the(2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl)boronic acid,(0.41 g, 2.0 mmol) and potassium carbonate (0.86 g, 6.2 mmol) in water(5 cm³). The solution was brought to reflux for 16 h then cooled to roomtemperature, poured into saturated ammonium chloride and extracted withEtOAc (×3). The combined organic extracts were dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,ethyl acetate:hexane 1:2.5) to afford the title compound (0.22 g, 0.68mmol, 51%) as a white solid: m.p. 200.2-202.0° C., ¹H NMR (DMSO-d₆) δ1.32 (s, 6H), 6.96 (d, J=8.1 Hz, 1H), 7.58 (dd, J=8.1, 1.8 Hz, 1H), 7.63(dd, J=7.8, 7.8 Hz, 1H), 7.75-7.78 (m, 2H), 7.98 (d, J=8.0 Hz, 1H), 8.15(s, 1H), 10.49 (s, 1H); MS (EI) m/z 263 (M+H)⁺.

Example 682-fluoro-3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzaldehydeoxime

A solution of 3-bromo-2-fluorobenzoic acid (0.219 g, 1 mmol) in drymethanol (5 ml) under nitrogen was treated with trimethylorthoformate(0.22 ml, 2 mmol) and p-toluenesulfonic acid (catalytic amount), andthen heated under reflux. After 16 h, the mixture was evaporated and theresidue partitioned between water and Et₂O. The organic layer washedwith sat. sodium hydrogen carbonate solution, water, brine, dried(MgSO₄) and evaporated to give methyl 3-bromo-2-fluorobenzoate (0.195 g,0.84 mmol, 84%): ¹H NMR (CDCl₃) δ 7.90-7.85 (m, 1H), 7.71-7.65 (m, 1H),7.10 (dt, 1H, J=8.0, 1.0 Hz) and 3.94 (s, 3H): MS (EI) 232 (M⁺).

A solution of the last cited compound (3.077 g, 13.2 mmol) in drytoluene (80 ml) at −78° C. under nitrogen was treated withdi-iso-butylaluminum hydride in toluene (1M, 15.7 ml, 15.7 mmol). After1 h at −78° C., the mixture was quenched with aqueous HCl (3M, 16 ml).The mixture was warmed to room temperature (RT), partitioned betweenEtOAc/H₂O, the aqueous layer was re-extracted with EtOAc, and thecombined organic layers were washed with water, dried (MgSO₄) andevaporated to afford 3-bromo-2-fluorobenzaldehyde (2.63 g, 12.9 mmol,98%), which was used without further purification: ¹H NMR (CDCl₃) δ10.35 (s, 1H), 7.82 (m, 2H), 7.18 (t, J=7.8 Hz).

A mixture of the last cited compound (2.63 g, 12.9 mmol), hydroxylaminehydrochloride (1.0 g, 14 mmol) and potassium acetate (1.37 g, 14 mmol)was placed in ethanol/H₂O (60 ml, 8:2) and the mixture was heated underreflux. After 30 min. the mixture was cooled, evaporated and partitionedbetween EtOAc and water. The organic layer washed with brine, dried(MgSO₄) and evaporated to give afford 3-bromo-2-fluorobenzaldoxime whichwas used without further characterization.

The title compound was prepared from 3-bromo-2-fluorobenzaldoxime (0.40g, 1.83 mmol) and(spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid asdescribed in example 18, to afford the product (0.094 g, 0.27 mmol, 15%yield) as a white solid: mp. 213-217° C.; ¹H NMR (CDCl₃) δ 10.95 (s,1H), 9.65 (s, 1H), 8.41 (s, 1H), 7.76 (t, 1H, J=7.1 Hz), 7.59 (s, 1H),7.43-7.33 (m, 3H), 7.19 (t, 1H, J=7.7 Hz), 6.98 (d, 1H, J=8 Hz) and1.91-1.60 (m, 10H); MS ((+) ESI) m/z=339 [M+H]⁺.

Example 69 5-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-4-methylthiophene-2-carbonitrile 5-Bromo-4-methyl-2-thiophene carboxaldehyde

To a solution of diethylamine (28 g, 0.383 mol) in anhydrous THF (400mL) was added at −40° C. under nitrogen a solution of n-BuLi (2.5 M, 153mL, 0.383 mol) in hexane. After addition, the solution was stirred at−40° C. under nitrogen for 30 minutes, cooled to −78° C. and treateddropwise with a solution of 2-bromo-3-methylthiophene (45 g, 0.254 mol)in anhydrous THF (450 mL). The reaction solution was stirred at −78° C.for 30 minutes and treated with anhydrous DMF (100 mL). The mixture wasallowed to warm to ambient temperature and was quenched with 1N aqueoushydrochloride solution (1 L). The solution was extracted with ethylacetate (3×450 mL). The extracts were washed with water, brine and dried(MgSO₄). After removal of solvent in vacuo, the subtitled compound wasobtained as a white solid (46 g, 88.3%). A sample of the product wascrystallized from hexane: mp 63-65° C.; IR (KBr) 1654 cm⁻¹. ¹H-NMR(CDCl₃) δ 9.75 (s, 1H), 7.45 (s, 1H), 2.26 (s, 3H); MS (EI) m/z 204/206(M⁺). Anal. Calc. For C₆H₅BrOS: C, 35.14; H, 2.46. Found: C, 35.00; H,2.44.

5-Bromo-4-methyl-2-thiophenecarbonitrile

Prepared from 5-bromo-4-methyl-2-thiophene carboxaldehyde using theprocedure of Example 35. White solid: mp 40-42° C.; IR (KBr) 2200 cm⁻¹;¹H-NMR (CDCl₃) δ 7.29 (s, 1H), 2.21 (s, 3H). MS (EI) m/z 201/203 (M⁺,98%/100%); Anal. Calc. For C₆H₄BrNS: C, 35.66; H, 1.99; N, 6.93. Found:C, 36.00; H, 2.14; N, 6.76.

Prepared according to the procedure for example 18 using(2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl)boronic acid(357 mg, 1.7 mmol) and 5-bromo-4-methylthiophene-2-carbonitrile (295 mg,1.5 mmol) to afford the title compound (227 mg, 0.8 mmol, 55%) as awhite solid: mp. 192.3-193° C., ¹H NMR (DMSO-d₆) δ 1.29 (s, 6H), 2.29(s, 3H), 6.97 (d, J=8.0 Hz, 1H), 7.34 (dd, J=8.0, 1.8 Hz, 1H), 7.49 (d,J=1.7 Hz, 1H), 7.84 (s, 1H), 10.57 (s, 1H); MS (EI) m/z 282 (M)⁺.

Example 705-(3-Chloro-5-fluoro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one

Prepared according to the procedure for example 18 for using(2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl)boronic acid(345 mg, 1.7 mmol) and 1-bromo-3-chloro-5-fluorobenzene (295 mg, 1.4mmol) to afford the title compound (245 mg, 0.85 mmol, 60%) as a whitesolid: mp. 205.9-206.8° C. ¹H NMR (DMSO-d₆) δ 1.31 (s, 6H), 6.93 (d,J=8.1 Hz), 7.35 (d, J=8.6 Hz, 1H), 7.5-7.6 (m, 2H), 7.6 (s, 1H), 7.78(d, J=1.4 Hz, 1H), 10.49 (s, 1H); MS (EI) m/z 290 (M+H)⁺.

Example 715-(3-Fluoro-5-nitro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one,

Prepared according to the procedure for example 18 using(2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl)boronic acid(272 mg, 1.3 mmol) and 1-fluoro-3-iodo-5-nitrobenzene (299 mg, 1.1 mmol)to afford the title compound (192 mg, 0.64 mmol, 57%) as a yellow solid:mp. 231.2-232.7° C., ¹H NMR (DMSO-d₆) δ 1.33 (s, 6H), 6.97 (d, J=8.1 Hz,1H), 7.67 (dd, J=8.1, 1.7 Hz, 1H), 7.88 (d, J=1.6 Hz, 1H), 8.0-8.1 (m,2H), 8.32 (s, 1H), 10.55 (s, 1H); MS (ESI) m/z 301 (M+H)⁺.

Example 724-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-furan-2-carbonitrile

Prepared according to the procedure for example 18 using(2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl)boronic acid(354 mg, 1.7 mmol) and 4-bromo-furan-2-carbonitrile (200 mg, 1.2 mmol)to afford the title compound (76 mg, 0.3 mmol, 26%) as a white solid:mp. 199.6-201.4° C., ¹H NMR (DMSO-d₆) δ 1.28 (s, 6H), 6.89 (d, J=8.0 Hz,1H), 7.48 (dd, J=8.0, 1.8 Hz, 1H), 7.65 (d, J=1.5 Hz, 1H), 8.1 (s, 1H),8.5 (s, 1H), 10.46 (s, 1H); MS (ESI) m/z 251 (M−H)⁻.

Example 734-Methyl-5-(2′-oxo-2′,3′-dihydrospiro[cyclopentane-1,3′-[3H]indol]-5′-yl)-2-thiophenecarbonitrile(Spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid

To a solution of 5-bromo-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one(13.1 g, 53 mmol) in anhydrous THF (300 cm³) under N₂, was added sodiumhydride (60% in mineral oil, 2.1 g, 53 mmol). After 30 minutes, thereaction mixture was cooled to −78° C. and butyl lithium (2.5 M inhexanes, 22 cm³, 53 mmol) was added slowly. After 30 minutes,tris-iso-propylborate (34 cm³, 146 mmol) was added, and the reactionmixture was slowly brought to room temperature, and stirred for 14hours. The reaction mixture was poured into 1N HCl and extracted withEtOAc (×3). The organic layers were collected and washed with 1N HCl,water, dried (MgSO₄) and evaporated to give the subtitled compound (7.8g, 64%) as a tan solid which was used without further purification. ¹HNMR (DMSO-d₆) δ 10.3 (s, 1H), 7.9 (s, 1H), 7.7-7.6 (m, 2H), 6.8 (d, 1H,J=7.7 Hz), 3.4 (s, 1H), 2.0-1.7 (m, 8H); MS (FI-POS) m/z @ 231.

A solution of 2-bromo-5-cyano-3-methylthiophene (0.63 g, 3.1 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycoldimethyl ether (20 cm³) was stirred under N₂ for 20 minutes. To thismixture was added(spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (1.0g, 4.7 mmol) and sodium carbonate (1.0 g, 9.4 mmol) in water (5 cm³).The solution was brought to reflux for 18 hours and then cooled to roomtemperature, poured into 2N NaOH and extracted with EtOAc (×3). Thecombined extracts were washed with water, brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,EtOAc, hexane) to afford the title compound (0.6 g, 62%) as apale-yellow solid. mp: 135-136° C.; ¹H NMR (DMSO-d₆) δ 10.5 (s, 1H), 7.8(s, 1H), 7.4-7.3 (m, 2H), 7.0 (d, 1H, J=8.0 Hz), 2.3 (s, 3H), 2.0-1.8(m, 8H); MS [M−H]⁻=307.

Example 745′-(4-Cyano-3-fluorophenyl)-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one

A solution of 4-cyano-3-fluoro-bromobenzene (0.63 g, 3.1 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycoldimethyl ether (20 cm³) was stirred under N₂ for 20 minutes. To thismixture was then added(spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (1.0g, 4.7 mmol) and sodium carbonate (1.0 g, 9.4 mmol) in water (5 cm³).The solution was brought to reflux for 18 hours and then cooled to roomtemperature, poured into 2N NaOH and extracted with EtOAc (×3). Thecombined extracts were washed with water, brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,EtOAc, hexane) to afford the title compound (0.35 g, 36%) as a yellowsolid. mp: dec. @ 235° C.; ¹H NMR (DMSO-d₆) δ 10.5 (s, 1H), 7.9 (t, 1H,J=7.6 Hz), 7.9 (dd, 1H, J=1.4, 10.2 Hz), 7.3 (td, 2H, J=1.6, 6.5 Hz),7.6 (dd, 1H, J=1.9, 6.3 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0-1.9 (m, 8H); MS[M−H]⁻=305.

Example 755′-(3-cyano-4-fluorophenyl)-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one

A solution of 3-cyano-4-fluoro-bromobenzene (0.63 g, 3.1 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycoldimethyl ether (20 cm³) was stirred under N₂ for 20 minutes. To thismixture was then added(spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (1.0g, 4.7 mmol) and sodium acetate (1.0 g, 9.4 mmol) in water (5 cm³). Thesolution was brought to reflux for 18 hours and then cooled to roomtemperature, poured into 2N NaOH and extracted with EtOAc (×3). Thecombined extracts were washed with water, brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,EtOAc, hexane) to afford the title compound (0.10 g, 10%) as whitecrystals. mp: 264-266° C.; ¹H NMR (DMSO-d₆) δ 10.4 (s, 1H), 8.3 (dd, 1H,J=2.4, 3.7 Hz), 8.1-8.0 (m, 1H), 7.6-7.5 (m, 2H), 7.5 (dd, 1H, J=1.9,6.3 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0-1.9 (m, 8H); MS [M−H]⁻=305.

Example 765′-(3-Chloro-4-fluorophenyl)-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one

A solution of 3-chloro-4-fluoro-bromobenzene (0.4 cm³, 0.66 g, 3.1mmol), and tetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethyleneglycol dimethyl ether (20 cm³) was stirred under N₂ for 20 minutes. Tothis mixture was then added(spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (1.0g, 4.7 mmol) and sodium carbonate (1.0 g, 9.4 mmol) in water (5 cm³).The solution was brought to reflux for 18 hours and then cooled to roomtemperature, poured into 2N NaOH and extracted with EtOAc (×3). Thecombined extracts were washed with water, brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,EtOAc, hexane) to afford the title compound (0.65 g, 66%) as apale-yellow solid. mp: 202-204° C.; ¹H NMR (DMSO-d₆) δ 10.4 (s, 1H), 7.9(dd, 1H, J=2.3, 4.9 Hz), 7.7-7.6 (m, 1H), 7.6 (d, 1H, J=1.5 Hz), 7.5 (s,1H), 7.4 (d, 1H, J=1.8 Hz), 6.9 (d, 1H, J=8.0 Hz), 2.0-1.9 (m, 8H); MS[M−H]⁻=314.

Example 77 5′-(3-Cyanophenyl)-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one

A solution of 3-bromobenzonitrile (0.5 g, 2.6 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycoldimethyl ether (20 cm³) was stirred under N₂ for 20 minutes. To thismixture was then added(spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (0.9g, 3.9 mmol) and sodium carbonate (0.8 g, 7.8 mmol) in water (5 cm³).The solution was brought to reflux for 18 hours and then cooled to roomtemperature, poured into 2N NaOH and extracted with EtOAc (×3). Thecombined extracts were washed with water, brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,EtOAc, hexane) to afford the title compound (0.30 g, 40%) as anoff-white solid. mp: 217-219° C.; ¹H NMR (DMSO-d₆) δ 10.4 (s, 1H), 8.2(s, 1H), 8.0 (d, 1H, J=8.1 Hz), 7.8 (d, 1H, J=7.7 Hz), 7.6 (m, 2H), 7.5(dd, 1H, J=1.8, 6.3 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0-1.9 (m, 8H); MS[M−H]⁻=287.

Example 785-(1,2-Dihydro-2-oxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-2-thiophenecarbonitrile

A solution of 2-bromo-5-cyanothiophene (0.5 g, 2.6 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycoldimethyl ether (20 cm³) was stirred under N₂ for 20 minutes. To thismixture was then added(spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (0.9g, 3.9 mmol) and sodium carbonate (0.8 g, 7.8 mmol) in water (5 cm³).The solution was brought to reflux for 18 hours and then cooled to roomtemperature, poured into 2N NaOH and extracted with EtOAc (×3). Thecombined extracts were washed with water, brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,EtOAc, hexane) to afford the title compound (0.3 g, 40%) as a yellowsolid. mp: 248° C.; ¹H NMR (DMSO-d₆) δ 10.4 (s, 1H), 8.5 (d, 1H, J=1.4Hz), 8.3 (d, 1H, J=1.4 Hz), 7.6 (s, 1H), 7.5 (dd, 1H, J=1.7, 6.4 Hz),6.9 (d, 1H, J=8.1 Hz), 2.0-1.8 (m, 8H); MS [M−H]⁻=293.

Example 795-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-furan-2-carbonitrile

A solution of 5-cyano-2-bromofuran (0.5 g, 2.6 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycoldimethyl ether (20 cm³) was stirred under N₂ for 20 minutes. To thismixture was then added(spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (0.9g, 3.9 mmol) and sodium carbonate (0.8 g, 7.8 mmol) in water (5 cm³).The solution was brought to reflux for 18 hours and then cooled to roomtemperature, poured into 2N NaOH and extracted with EtOAc (×3). Thecombined extracts were washed with water, brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,EtOAc, hexane) to afford the title compound (0.35 g, 49%) as anoff-white solid. mp: 193-194° C.; ¹H NMR (DMSO-d₆) δ 10.6 (s, 1H), 7.7(d, 2H, J=3.3 Hz), 7.6 (dd, 1H, J=1.6, 6.6 Hz), 7.1 (d, 1H, J=3.8 Hz),6.9 (d, 1H, J=8.1 Hz), 2.0-1.8 (m, 8H); MS [M−H]⁻=277.

Example 805′-(3-Cyano-5-fluorophenyl)-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one

A solution of 3-cyano-5-fluoro-bromobenzene (0.5 g, 2.6 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycoldimethyl ether (20 cm³) was stirred under N₂ for 20 minutes. To thismixture was then added(spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (0.9g, 3.9 mmol) and sodium carbonate (0.8 g, 7.8 mmol) in water (5 cm³).The solution was brought to reflux for 18 hours and then cooled to roomtemperature, poured into 2N NaOH and extracted with EtOAc (×3). Thecombined extracts were washed with water, brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,EtOAc, hexane) to afford the title compound (0.35 g, 44%) as whiteneedles. mp: 235-237° C.; ¹H NMR (DMSO-d₆) δ 10.5 (s, 1H), 8.1 (s, 1H),8.0 (dt, 1H, J=1.7, 2.0, 7.0 Hz), 7.8-7.7 (m, 2H), 7.6 (dd, 1H, J=1.8,6.4 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0-1.9 (m, 8H); MS (EI) M⁺ @ m/z 306.

Example 813-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)phenylacetonitrile

Prepared from 3-bromophenylacetonitrile and2′-oxo-2′,3,-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)boronic acidaccording to the procedure for example 18 to afford the title compoundas a white powder; mp. 190-193° C.; ¹H-NMR (DMSO-d₆) δ 10.42 (s, 1H),7.67 (d, 1H, J=1.39 Hz), 7.58 (d, 2H, J=6.87 Hz), 7.46 (m, 2H), 7.31 (d,1H J=7.6 Hz), 6.94 (d, 1H, J=8.05 Hz), 4.10 (s, 2H) 2.04-1.50 (m, 10H);MS m/z 316 (M+.). Anal. Calc. For C₂₁H₂₀N₂O₂0.2H₂O: C, 78.82, H, 6.42;N, 8.75. Found: C, 78.73, H, 6.44; N, 8.52.

Example 823-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-5-fluoro-benzonitrile

Prepared according to the procedure for example 18 using(2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl)boronic acid(640 mg, 3.1 mmol) and 5-bromo-3-cyano-fluorobenzene (423 mg, 21.2 mmol)to afford the title compound (261 mg, 0.93 mmol, 44%) as a yellow solid:mp. 231.2-232.3° C., ¹H NMR (DMSO-d₆) δ 1.32 (s, 6H), 6.95 (d, J=8.0 Hz,1H), 7.64 (dd, J=8.1, 1.8 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.85 (d,J=1.6 Hz, 1H), 7.93 (d, J=8.6 Hz, 1H), 8.07 (s, 1H), 10.52 (s, 1H); MS(EI) m/z 280 (M)⁺.

Example 833,3-Dimethyl-5-(5-nitro-thiophene-2-yl)-1,3-dihydro-indol-2-one

Prepared according to the procedure for example 18 using(2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl)boronic acid(384 mg, 1.9 mmol) and 2-bromo-5-nitrothiophene (300 mg, 1.4 mmol) toafford the title compound (270 mg, 0.9 mmol, 65%) as a yellow brownsolid: mp. 223-225° C., ¹H NMR (CDCl₃) δ 1.5 (s, 6H), 6.99 (d, J=8.1 Hz,1H), 7.18 (d, J=4.3 Hz, 1H), 7.44 d, J=1.7 Hz, 1H), 7.51 (dd, J=8.1, 1.9Hz, 1H), 7.91 (d, J=4.3 Hz, 1H), 8.07 (br s, 1H); MS (EI) m/z 288 (M)⁺.

Example 842-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyrrole-1-carboxylicacid tert-butyl ester

Prepared according to the procedure for example 18 using5′-bromo-3,3-dimethyl-[1,3′-[3H]indol]-2′-(1′H)-one (1.24 g, 5.2 mmol)and N—BOC-pyrrole-2-boronic acid (1.5 g, 5.93 mmol) to afford the titlecompound (506 mg, 1.5 mmol, 30%) as off-white solid: mp. 168.4-170.2°C., ¹H NMR (DMSO-d₆) δ 1.26 (s, 6H), 1.28 (s, 9H), 6.1 (dd, J=3.2, 1.8Hz, 1H), 6.2 (dd, J=3.2, 3.2 Hz, 1H), 6.8 (d, J=7.9 Hz, 1H), 7.1 (dd,J=7.9, 1.6 Hz, 1H), 7.2 (d, J=1.6 Hz, 1H), 7.3 (dd, J=3.2, 1.8 Hz, 1H),10.4 (s, 1H); MS (APCI) m/z 327 (M+H)⁺.

Example 852-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2-nitro-pyrrole

To a solution of2-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyrrole-1-carboxylicacid tert-butyl ester (0.90 g, 2.8 mmol) in acetonitrile (anhydrous, 40mL) at −15° C. was added silver nitrate (0.49 g, 2.9 mmol) followed byacetyl chloride (0.21 mL, 2.95 mmol). The reaction was allowed to warmto room temperature and stirred 16 h. Dichloromethane (250 mL) was addedto the reaction mixture; filtered through celite and washed with water,saturated sodium bicarbonate, water then brine dried over magnesiumsulfate, filtered and concentrated in vacuo. Purification via flashcolumn chromatography on silica gel (2:3 ethyl acetate/hexane) gave2-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2-nitro-pyrrole-1-carboxylicacid tert-butyl ester as a yellow solid: ¹H NMR (CDCl₃) δ 1.43 (s, 6H),1.48 (s, 9H), 6.3 (d, J=4.1 Hz, 1H), 7.0 (d, J=8.0 Hz, 1H), 7.2 (d,J=4.1 Hz, 1H), 7.34 (d, J=1.7 Hz, 1H), 7.4 (dd, J=8.0, 1.7 Hz, 1H), 8.2(s, 1H).

2-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2-nitro-pyrrole-1-carboxylicacid tert-butyl ester, was placed in a 50 mL round bottomed flask undernitrogen. A vigorous flow of nitrogen was maintained as the flask wasplaced in an oil bath and heated to 160° C. After 10 min at thistemperature, the flask was removed from the oil bath and allowed tocool. The black residue washed into a larger flask with acetone andadsorbed onto a small amount of florisil. Purification by flash columnchromatography on silica gel (1:2 EtOAc:hexane) to afford the titlecompound (76 mg, 15%) which was triturated from ether/hexane to providea greenish-yellow solid, mp 293.9-294.2° C. (dec). ¹H NMR (DMSO-d₆) δ1.3 (s, 6H), 6.77 (d, J=4.3 Hz, 1H), 6.91 (d, J=8.1 Hz, 1H), 7.26 (d,J=4.3 Hz, 1H), 7.78 (dd, J=8.1, 1.8 Hz, 1H), 7.96 (d, J=1.8 Hz, 1H),10.55 (s, 1H), 13.12 (s, 1H); MS (ESI) m/z 270 (M−H)⁻.

Example 865-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-thiophene-2-carbonitrile

Prepared according to the procedure for example 18 using(2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl)boronic acid(570 mg, 2.8 mmol) and 5-bromo-thiophene-2-carbonitrile (350 mg, 1.9mmol) to afford the title compound (299 mg, 1.1 mmol, 60%) as anoff-white solid: mp. 255-256° C., ¹H NMR (CDCl₃) δ ¹H NMR (CDCl₃) δ 1.46(s, 6H), 6.97 (d, J=8.1 Hz, 1H), 7.21 (d, J=3.9 Hz, 1H), 7.39 (d, J=1.3Hz, 1H), 7.47 (dd, J=8.1, 1.8 Hz, 1H), 7.58 (d, J=3.9 Hz, 1H), 8.14 (s,1H); MS (EI) m/z 268 (M)⁺.

Example 873-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2-fluoro-benzonitrile

Prepared according to the procedure for example 18 using(2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl)boronic acid(300 mg, 1.5 mmol) and 4-bromo-2-fluoro-benzonitrile (240 mg, 1.2 mmol)to afford the title compound (185 mg, 0.66 mmol, 55%) as an off whitesolid: mp. 270-272° C., ¹H NMR (DMSO-d₆) δ 1.31 (s, 6H), 6.96 (d, J=8.1Hz, 1H), 7.67 (dd, J=8.1, 1.8 Hz, 1H), 7.74 (dd, J=8.2, 1.5 Hz, 1H),7.85 (s, 1H), 7.89 (d, J=1.3 Hz, 1H), 7.96 (dd, J=7.5, 7.5 Hz, 1H),10.56 (s, 1H); MS (ESI) m/z 279 (M−H)⁻.

Example 88 Pharmacology

The biological activity for the compounds of the current invention wasevaluated in the in-vitro and in-vivo assays described below. In-vitropotencies lie in the range 0.01 nM-10,000 nM, and in-vivo potencies inthe range 1 μg/kg to 100 mg/kg.

A. In-Vitro Biology

-   -   The in-vitro biology is determined by (1) competitive        Radioligand Binding: using the A-form of the human progesterone        receptor with progesterone as the radioligand; (2)        co-transfection assay, which provides functional activity        expressed as agonist EC50 and Antagonist IC50 values; (3) a T47D        cell proliferation, which is a further functional assay which        also provides agonist and antagonist data; and (4) T47D cell        alkaline phosphatase assay, which is a further functional assay        which also provides agonist and antagonist data.    -   1. hPR Binding assay—This assay is carried out in accordance        with: Pathirana, C.; Stein, R. B.; Berger, T. S.; Fenical, W.;        Ianiro, T.; Mais, D. E.; Torres, A.; Glodman, M. E.,        Nonsteroidal human progesterone receptor modulators from the        marine alga cymoplia barbata, J. Steroid Biochem. Mol. Biol.,        1992, 41, 733-738.    -   2. PRE-luciferase assay in CV-1 cells—The object of this assay        is to determine a compound's progestational or        antiprogestational potency based on its effect on PRE-luciferase        reporter activity in CV-1 cells co-transfected with human PR and        PRE-luciferase plasmids. The materials methods used in the assay        are as follows.        -   a. Medium: The growth medium was as follows: DMEM            (BioWhittaker) containing 10% (v/v) fetal bovine serum (heat            inactivated), 0.1 mM MEM non-essential amino acids, 100 U/ml            penicillin, 100 mg/ml streptomycin, and 2 mM GlutaMax            (GIBCO, BRL).            -   The experimental medium was as follows: DMEM                (BioWhittaker), phenol red-free, containing 10% (v/v)                charcoal-stripped fetal bovine serum (heat-inactivated),                0.1 mM MEM non-essential amino acids, 100 U/ml                penicillin, 100 mg/ml streptomycin, and 2 mM GlutaMax                (GIBCO, BRL).        -   b. Cell culture, transfection, treatment, and luciferase            assay            -   Stock CV-1 cells are maintained in growth medium.                Co-transfection is done using 1.2×10⁷ cells, 5 mg pLEM                plasmid with hPR-B inserted at Sph1 and BamH1 sites, 10                mg pGL3 plasmid with two PREs upstream of the luciferase                sequence, and 50 mg sonicated calf thymus DNA as carrier                DNA in 250 ml. Electroporation is carried out at 260 V                and 1,000 mF in a Biorad Gene Pulser II. After                electroporation, cells are resuspended in growth medium                and plated in 96-well plate at 40,000 cells/well in 200                μl. Following overnight incubation, the medium is                changed to experimental medium. Cells are then treated                with reference or test compounds in experimental medium.                Compounds are tested for antiprogestational activity in                the presence of 3 nM progesterone. Twenty-four hr. after                treatment, the medium is discarded, cells are washed                three times with D-PBS (GIBCO, BRL). Fifty μl of cell                lysis buffer (Promega, Madison, Wis.) is added to each                well and the plates are shaken for 15 min in a Titer                Plate Shaker (Lab Line Instrument, Inc.). Luciferase                activity is measured using luciferase reagents from                Promega.        -   c. Analysis of Results:            -   Each treatment consists of at least 4 replicates. Log                transformed data are used for analysis of variance and                nonlinear dose response curve fitting for both agonist                and antagonist modes. Huber weighting is used to                downweight the effects of outliers. EC₅₀ or IC₅₀ values                are calculated from the retransformed values. JMP                software (SAS Institute, Inc.) is used for both one-way                analysis of variance and non-linear response analyses.        -   d. Reference Compounds:            -   Progesterone and trimegestone are reference progestins                and RU486 is the reference antiprogestin. All reference                compounds are run in full dose-response curves and the                EC₅₀ or IC₅₀ values are calculated.

TABLE 1 Estimated EC₅₀, standard error (SE), and 95% confidenceintervals (CI) for reference progestins from three individual studiesEC₅₀ 95% CI Compound Exp. (nM) SE lower upper Progesterone 1 0.616 0.0260.509 0.746 2 0.402 0.019 0.323 0.501 3 0.486 0.028 0.371 0.637Trimegestone 1 0.0075 0.0002 0.0066 0.0085 2 0.0081 0.0003 0.0070 0.00943 0.0067 0.0003 0.0055 0.0082

TABLE 2 Estimated IC₅₀, standard error (SE), and 95% confident interval(CI) for the antiprogestin, RU486 from three individual studies IC₅₀ 95%CI Compound Exp. (nM) SE lower upper RU486 1 0.028 0.002 0.019 0.042 20.037 0.002 0.029 0.048 3 0.019 0.001 0.013 0.027

Progestational activity: Compounds that increase PRE-luciferase activitysignificantly (p<0.05) compared to vehicle control are consideredactive.

Antiprogestational activity: Compounds that decrease 3 nM progesteroneinduced PRE-luciferase activity significantly (p<0.05)

EC₅₀: Concentration of a compound that gives half-maximal increasePRE-luciferase activity (default-nM) with SE.

IC₅₀: Concentration of a compound that gives half-maximal decrease in 3nM progesterone induced PRE-luciferase activity (default-nM) with SE.

-   -   3. T47D cell proliferation assay—The objective of this assay is        the determination of progestational and antiprogestational        potency by using a cell proliferation assay in T47D cells. A        compound's effect on DNA synthesis in T47D cells is measured.        The materials and methods used in this assay are as follows.        -   a. Growth medium: DMEM:F12 (1:1) (GIBCO, BRL) supplemented            with 10% (v/v) fetal bovine serum (not heat-inactivated),            100 U/ml penicillin, 100 mg/ml streptomycin, and 2 mM            GlutaMax (GIBCO, BRL).        -   b. Treatment medium: Minimum Essential Medium (MEM)            (#51200-038GIBCO, BRL) phenol red-free supplemented with            0.5% charcoal stripped fetal bovine serum, 100 U/ml            penicillin, 200 mg/ml streptomycin, and 2 mM GlutaMax            (GIBCO, BRL).        -   c. Cell culture: Stock T47 D cells are maintained in growth            medium. For BrdU incorporation assay, cells are plated in            96-well plates (Falcon, Becton Dickinson Labware) at 10,000            cells/well in growth medium. After overnight incubation, the            medium is changed to treatment medium and cells are cultured            for an additional 24 hr before treatment. Stock compounds            are dissolved in appropriate vehicle (100% ethanol or 50%            ethanol/50% DMSO), subsequently diluted in treatment medium            and added to the cells. Progestin and antiprogestin            reference compounds are run in full dose-response curves.            The final concentration of vehicle is 0.1%. In control            wells, cells receive vehicle only. Antiprogestins are tested            in the presence of 0.03 nM trimegestone, the reference            progestin agonist. Twenty-four hours after treatment, the            medium is discarded and cells are labeled with 10 mM BrdU            (Amersham Life Science, Arlington Heights, Ill.) in            treatment medium for 4 hr.        -   d. Cell Proliferation Assay: At the end of BrdU labeling,            the medium is removed and BrdU incorporation is measured            using a cell proliferation ELISA kit (#RPN 250, Amersham            Life Science) according to manufacturer's instructions.            Briefly, cells are fixed in an ethanol containing fixative            for 30 min, followed by incubation in a blocking buffer for            30 min to reduce background. Peroxidase-labeled anti-BrdU            antibody is added to the wells and incubated for 60 min. The            cells are rinsed three times with PBS and incubated with            3,3′5,5′-tetramethylbenzidine (TMB) substrate for 10-20 min            depending upon the potency of tested compounds. Then 25 μl            of 1 M sulfuric acid is added to each well to stop color            reaction and optical density is read in a plate reader at            450 nm within 5 min.        -   e. Analysis of Results:            -   Square root-transformed data are used for analysis of                variance and nonlinear dose response curve fitting for                both agonist and antagonist modes. Huber weighting is                used to downweight the effects of outliers. EC₅₀ or IC₅₀                values are calculated from the retransformed values. JMP                software (SAS Institute, Inc.) is used for both one-way                analysis of variance and non-linear dose response                analyses in both single dose and dose response studies.        -   f. Reference Compounds: Trimegestone and medroxyprogesterone            acetate (MPA) are reference progestins and RU486 is the            reference antiprogestin. All reference compounds are run in            full dose-response curves and the EC₅₀ or IC₅₀ values are            calculated.

TABLE 3 Estimated EC₅₀, standard error (SE), and 95% confidenceintervals (CI) for individual studies EC₅₀ 95% CI Compound Exp (nM) SElower upper Trimegestone 1 0.017 0.003 0.007 0.040 2 0.014 0.001 0.0110.017 3 0.019 0.001 0.016 0.024 MPA 1 0.019 0.001 0.013 0.027 2 0.0170.001 0.011 0.024

TABLE 4 Estimated IC₅₀, standard error, and 95% confident interval forthe antiprogestin, RU486 IC₅₀ 95% CI Compound Exp (nM) SE lower upperRU486 1 0.011 0.001 0.008 0.014 2 0.016 0.001 0.014 0.020 3 0.018 0.0010.014 0.022EC₅₀: Concentration of a compound that gives half-maximal increase inBrdU incorporation with SE;. IC₅₀: Concentration of a compound thatgives half-maximal decrease in 0.1 trimegestone induced BrdUincorporation with SE

-   -   4. T47D cell alkaline phosphatase assay—The purpose of this        assay is to identify progestins or antiprogestins by determining        a compound's effect on alkaline phosphatase activity in T47D        cells. The materials and methods used in this assay are as        follows.        -   a. Culture medium: DMEM:F12 (1:1) (GIBCO, BRL) supplemented            with 5% (v/v) charcoal stripped fetal bovine serum (not            heat-inactivated), 100 U/ml penicillin, 100 μg/ml            streptomycin, and 2 mM GlutaMax (GIBCO, BRL).        -   b. Alkaline phosphatase assay buffer:            -   I. 0.1 M Tris-HCl, pH 9.8, containing 0.2% Triton X-100            -   II. 0.1 M Tris-HCl, pH 9.8 containing 4 mM p-nitrophenyl                phosphate (Sigma).        -   c. Cell Culture and Treatment: Frozen T47D cells were thawed            in a 37° C. water bath and diluted to 280,000 cells/ml in            culture medium. To each well in a 96-well plate (Falcon,            Becton Dickinson Labware), 180 μl of diluted cell suspension            was added. Twenty μl of reference or test compounds diluted            in the culture medium was then added to each well. When            testing for progestin antagonist activity, reference            antiprogestins or test compounds were added in the presence            of 1 nM progesterone. The cells were incubated at 37° C. in            a 5% CO₂/humidified atmosphere for 24 hr.        -   d. Alkaline Phosphatase Enzyme Assay:            -   At the end of treatment, the medium was removed from the                plate and fifty μl of assay buffer I was added to each                well. The plates were shaken in a titer plate shaker for                15 min. Then 150 μl of assay buffer II was added to each                well. Optical density measurements were taken at 5 min                intervals for 30 min at a test wavelength of 405 nM.        -   e. Analysis of Results: Analysis of dose-response data            -   For reference and test compounds, a dose response curve                is generated for dose (X-axis) vs. the rate of enzyme                reaction (slope) (Y-axis). Square root-transformed data                are used for analysis of variance and nonlinear dose                response curve fitting for both agonist and antagonist                modes. Huber weighting is used to downweight the effects                of outliers. EC₅₀ or IC₅₀ values are calculated from the                retransformed values. JMP software (SAS Institute, Inc.)                is used for both one-way analysis of variance and                non-linear dose response analyses in both single dose                and dose response studies.        -   f. Reference Compounds: Progesterone and trimegestone are            reference progestins and RU486 is the reference            antiprogestin. All reference compounds are run in full dose            response curves and the EC₅₀ or IC₅₀ values are calculated.

TABLE 5 Estimated EC₅₀, standard error (SE), and 95% confidenceintervals (CI) for reference progestins from three independentexperiments EC₅₀ 95% CI Compound Exp. (nM) SE lower upper Progesterone 10.839 0.030 0.706 0.996 2 0.639 0.006 0.611 0.669 3 1.286 0.029 1.1581.429 Trimegestone 1 0.084 0.002 0.076 0.091 2 0.076 0.001 0.072 0.080 30.160 0.004 0.141 0.181

TABLE 6 Estimated IC₅₀, standard error, and 95% confident interval forthe reference antiprogestin RU486 from three independent experimentsIC₅₀ 95% CI Compound Exp (nM) SE lower upper RU486 1 0.103 0.002 0.0920.115 2 0.120 0.001 0.115 0.126 3 0.094 0.007 0.066 0.134

B. In-vivo Biology

-   -   The primary in-vivo assay is the rat decidualization model which        may be used to determine progestational effects of both agonists        and antagonists. The secondary in-vivo assay is the rat        ovulation inhibition model which is under development and hence        the protocol is un-available.    -   1. Rat decidualization assay—The objective of this procedure is        used to evaluate the effect of progestins and antiprogestins on        rat uterine decidualization and compare the relative potencies        of various test compounds. The materials and methods used in        this assay are as follows.        -   a. Methods: Test compounds are dissolved in 100% ethanol and            mixed with corn oil (vehicle). Stock solutions of the test            compounds in oil (Mazola™) are then prepared by heating            (˜80° C.) the mixture to evaporate ethanol. Test compounds            are subsequently diluted with 100% corn oil or 10% ethanol            in corn oil prior to the treatment of animals. No difference            in decidual response was found when these two vehicles were            compared.        -   b. Animals (RACUC protocol #5002): Ovariectomized mature            female Sprague-Dawley rats (˜60-day old and 230 g) are            obtained from Taconic (Taconic Farms, N.Y.) following            surgery. Ovariectomy is performed at least 10 days prior to            treatment to reduce circulating sex steroids. Animals are            housed under 12 hr light/dark cycle and given standard rat            chow and water ad libitum.        -   c. Treatment            -   Rats are weighed and randomly assigned to groups of 4 or                5 before treatment. Test compounds in 0.2 ml vehicle are                administered by subcutaneous injection in the nape of                the neck or by gavage using 0.5 ml. The animals are                treated once daily for seven days. For testing                antiprogestins, animals are given the test compounds and                an EC₅₀ dose of progesterone (5.6 mg/kg) during the                first three days of treatment. Following decidual                stimulation, animals continue to receive progesterone                until necropsy four days later.        -   d. Dosing            -   Doses are prepared based upon mg/kg mean group body                weight. In all studies, a control group receiving                vehicle is included. Determination of dose-response                curves is carried out using doses with half log                increases (e.g. 0.1, 0.3, 1.0, 3.0 mg/kg . . . ).        -   e. Decidual induction            -   Approximately 24 hr after the third injection,                decidualization is induced in one of the uterine horns                by scratching the antimesometrial luminal epithelium                with a blunt 21 G needle. The contralateral horn is not                scratched and serves as an unstimulated control.                Approximately 24 hr following the final treatment, rats                are sacrificed by CO₂ asphyxiation and body weight                measured. Uteri are removed and trimmed of fat.                Decidualized (D-horn) and control (C-horn) uterine horns                are weighed separately.        -   f. Analysis of Results:            -   The increase in weight of the decidualized uterine horn                is calculated by D-horn/C-horn and logarithmic                transformation is used to maximize normality and                homogeneity of variance. The Huber M-estimator is used                to down weight the outlying transformed observations for                both dose-response curve fitting and one-way analysis of                variance. JMP software (SAS Institute, Inc.) is used for                both one-way ANOVA and non-linear dose-response                analyses.        -   g. Reference Compounds:            -   All progestin reference compounds were run in full                dose-response curves and the EC₅₀ for uterine wet weight                were calculated.

TABLE 7 Estimated EC₅₀, standard error (SE), and 95% confidenceintervals for individual studies EC₅₀ 95% CI Compound Exp (mg/kg, s.c.)SE lower upper Progesterone 1 5.50 0.77 4.21 7.20 2 6.21 1.12 4.41 8.763-Ketodesogestrel 1 0.11 0.02 0.07 0.16 2 0.10 0.05 0.11 0.25 3 0.060.03 0.03 0.14 Levonorgestrel 1 0.08 0.03 0.04 0.16 2 0.12 0.02 0.090.17 3 0.09 0.02 0.06 0.13 4 0.09 0.02 0.06 0.14 MPA 1 0.42 0.03 0.290.60 2 0.39 0.05 0.22 0.67 3 0.39 0.04 0.25 0.61

TABLE 8 Estimated average EC₅₀, standard error, and 95% confidenceintervals for dose-response curves of 3 reference compounds EC₅₀ 95% CICompound (mg/kg, s.c.) SE lower upper Progesterone 5.62 0.62 4.55 7.003-Ketodesogestrel 0.10 0.02 0.07 0.14 Levonorgestrel 0.10 0.01 0.08 0.12

TABLE 9 Estimated IC₅₀, standard error, and 95% confident interval forthe antiprogestin, RU 486 IC₅₀ 95% CI Compound Exp. (mg/kg, p.o.) SElower upper RU 486 1 0.21 0.07 0.05 0.96 2 0.14 0.02 0.08 0.27

Concentration: Compound concentration in assay (default-mg/kg bodyweight)

Route of administration: Route the compound is administered to theanimals

Body weight: Mean total animal body weight (default-kg)

D-horn: Wet weight of decidualized uterine horn (default-mg)

C-horn: Wet weight of control uterine horn (default-mg)

Decidual response: [(D−C)/C]×100%

Progestational activity: Compounds that induce decidualizationsignificantly (p<0.05) compared to vehicle control are considered active

Antiprogestational activity: Compounds that decrease EC₅₀ progesteroneinduced decidualization significantly (p<0.05)

EC₅₀ for uterine weight: Concentration of compound that giveshalf-maximal increase in decidual response (default-mg/kg)

IC₅₀ for uterine weight: Concentration of compound that giveshalf-maximal decrease in EC₅₀ progesterone induced decidual response(default-mg/kg)

Data for Representative Compounds Decid. IC₅₀ Example # Ki/nM CV-1IC₅₀/nM mg/kg 34 19 14 50% @ 10 35 22 19 50% @ 10 80 70% # 3 77 60% @ 344 123 20 50% @ 3 73 50% @ 3 36 4.8 9 50% @ 10 32 9 1 60% @ 10 47 18 750% @ 10

Example 894-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-fluorobenzeneacetonitrile

Prepared from 4-bromo-2-fluorophenylacetonitrile and(2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)boronicacid according to the procedure for example 18 to afford the titlecompound as a white solid; mp. 180-183° C.; ¹H-NMR (DMSO-d₆) δ 10.4 (s,1H), 7.7 (s, 1H), 7.6-7.7 (m, 4H) 6.9 (d, 1H, J=8.1 Hz), 4.1 (s, 2H),1.9 (m, 2H), 1.7-1.6 (m, 8H). MS (APCI (−)) m/z 333 [M−H]⁻ Anal. calc.for C₂₁H₁₉FN₂O.0.5H₂O: C, 73.49, H, 5.87; N, 8.20. Found: C, 73.55, H,5.50; N, 7.36.

Example 905-(3-Fluoro-4-methoxyphenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

Prepared from 4-bromo-2-fluoroanisole and(2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)boronicacid according to the procedure for example 18 to afford the titlecompound as a white solid, mp. 178-180° C.; ¹H-NMR (DMSO-d₆) δ 10.4 (s,1H), 7.65 (d, 1H, J=1.1 Hz), 7.5-7.4 (m, 3H), 7.2 (t, 1H, J=8.9 Hz), 6.9(d, 1H, J=8 Hz), 3.9 (s, 3H), 1.9 (m, 2H) 1.7-1.6 (m, 8H); MS (APCI (−))m/z 324 [M−H]⁻; Anal. Calc. For C₂₀H₂₀FNO₂: C, 73.83, H, 6.20; N, 4.30.Found: C, 73.55, H, 6.23; N, 4.40.

Example 91 5-(3-Chlorophenyl)spiro[cyclobutane-1,3-[3H]indole]-2(1H)-one5-Bromospiro[cyclobutane-1,3-[3H]indol]-2(1H)-one

To a stirred solution of spiro[cyclobutane-1,3′-[3H]indol]-2′(1′H)-one(J. Med. Chem. 1987, 824-9) (1.0 g, 6 mmol) in glacial acetic acid (10mL) was added dropwise at room temperature a solution of bromine (0.30mL, 6 mmol) in glacial acetic acid (6 mL). After stirring for 10 min,anhydrous sodium acetate (0.47 g, 6 mmol) was added and the solution wasconcentrated in vacuo. The residue was dissolved in ethyl ether (50 mL)and washed sequentially with water (50 mL), aqueous saturated sodiumbicarbonate solution (50 mL), water (50 mL) and brine (30 mL). Theorganic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo. Crystallization from ethyl ether yielded theproduct as a white fluffy solid (1.1 g, 73%), mp 235-7° C.; ¹H NMR(DMSO-d₆, 300 MHz) δ2.15-2.41 (m, 6H), 6.74 (d, 1H, J=8.2 Hz), 7.33 (dd,1H, J=2, 8.2 Hz), 7.75 (d, 1H, J=2 Hz), 10.36 (bs, 1H); MS (EI) m/z 251[M⁺]; Anal. Calcd for C₁₁H₁₀BrNO: C, 52.41; H, 4.00; N, 5.56. Found: C,51.98; H, 4.24; N, 5.42.

To a solution of 5-bromospiro[cyclobutane-1,3-[3H]indol]-2(1H)-one (0.6g, 2 mmol) in ethylene glycol dimethyl ether (50 mL) under a nitrogenatmosphere was added tetrakis(triphenylphosphine)palladium(0) (140 mg,0.1 mmol). To the solution was added sequentially 3-chlorophenyl boronicacid (0.48 g, 3 mmol) and potassium carbonate (0.76 g, 5 mmol) in water(5 mL). The mixture was heated to 80° C. for 3 h and allowed to cool.The reaction mixture was poured into water (100 mL) and extracted withethyl acetate (3×100 mL). The organic layers were combined, washed withbrine (50 mL) and dried over magnesium sulfate. The solution wasfiltered, concentrated in vacuo, and the residue was purified by HPLC(Zorbax PRO, C18, 10u, 15A, 50×250 mm; 35% Water/65% AcCN; 254 NM; AMB.temp.) to give the title compound (200 mg, 35%) as a white powder, mp199.5-201° C. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.21-2.28 (m, 2H), 2.40-2.45(m, 4H), 6.87 (d, 1H, J=8.1 Hz), 7.37 (‘d’, 1H), 7.44-7.52 (m, 2H), 7.65(bd, 1H, J=7.8 Hz), 7.76 (bs, 1H), 7.92 (bs, 1H), 10.35 (s, 1H). MS (EI)m/z 283 [M⁺]. Anal. Calcd for C₁₇H₁₄ClNO: C, 71.96; H, 4.97; N, 4.94.Found: C, 70.75; H, 5.07; N, 4.68.

Example 925-(3-Chlorophenyl)spiro[cyclopropane-1,3-[3H]indole]-2(1H)-one

To 5-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (1.2 g, 5 mmol) intetrahydrofuran (25 mL, anhydrous) at −20° C. was added slowlyn-butyllithium (2.5 M solution in hexanes, 3.93 mL, 9.8 mmol), followedby N,N,N′,N′-tetramethylethylenediamine (1.48 mL, 9.8 mmol). After 15min, 1,2-dibromoethane (1.27 mL, 15 mmol) was added slowly and themixture was allowed to reach room temperature. After 5 days, saturatedaqueous ammonium chloride solution (50 mL) and ethyl acetate (50 mL)were added. The layers were separated and the aqueous phase wasextracted with ethyl acetate (2×25 mL). The organic layers werecombined, washed with 1 N HCl (25 mL) and brine (25 mL), and dried overmagnesium sulfate. The solution was filtered and concentrated in vacuo.The residue was purified by flash column chromatography (40% ethylacetate/hexane) on a pad of silica gel to give the product (40 mg) aswhite crystals, mp 212-214° C.; ¹H NMR (CDCl₃, 300 MHz) δ 1.59-1.63 (m,2H), 1.80-1.84 (m, 2H), 7.00-7.03 (m, 2H), 7.28-7.42 (m, 4H), 7.51 (‘t’,1H), 7.85 (bs, 1H). MS (EI) m/z 269 [M⁺]. Anal. Calcd for C₁₆H₁₂ClNO: C,71.25; H, 4.48; N, 5.19. Found: C, 70.78; H, 4.88; N, 5.10.

Example 932-Nitro-5-(1,2-dihydro-2-oxospiro[cyclobutane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester 1-t-Butoxycarbonylpyrrole-2-boronic acid

To 1-tert-butyl pyrrolecarboxylate (Aldrich, 25 g, 0.15 mol, 1.0 eq) inTHF at −78° C. (anhydrous, 250 mL) was added LDA (2 M solution inheptane/THF/ethylbenzene, 82 mL, 1.1 eq). After stirring for 30 min at−78° C., trimethylborate (85 mL, 0.750 mol, 5.0 eq) was added. Afterstirring at −78° C. for 1 h, the dry ice bath was removed and thereaction was allowed to come to room temperature overnight. HCl (0.25 N,200 mL) was added to the reaction and the THF was removed in vacuo. Theaqueous layer was extracted with ethyl ether (3×300 mL). The combinedether layers were washed with water (2×200 mL), then with brine (200mL), and dried over magnesium sulfate. The solution was filtered andconcentrated in vacuo. When the product began to crystallize on therotary, the flask was removed and allowed to stand. The crystals werefiltered and washed with ice-cold ethyl ether to give the product (14 g,44%) as a white solid. Several crystallizations of filtrate from coldether gave more product (4.5 g, 14%).

5-(1,2-dihydro-2-oxospiro[cyclobutane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester

To a solution of 5-Bromospiro[cyclobutane-1,3-[3H]indol]-2(1H)-one (0.6g, 2.4 mmol) in ethylene glycol dimethyl ether (50 mL) under a nitrogenatmosphere was added tetrakis(triphenylphosphine)palladium(0) (140 mg,0.1 mmol). To the solution was added sequentially1-t-butoxycarbonylpyrrole-2-boronic acid (0.65 g, 3.1 mmol) andpotassium carbonate (0.75 g, 5.4 mmol) in water (5 mL). The mixture washeated to 80° C. for 3 h and allowed to cool. The reaction mixture waspoured into water (100 mL) and extracted with ethyl acetate (3×100 mL).The organic layers were combined, washed with brine (50 mL) and driedover magnesium sulfate. The solution was filtered, concentrated invacuo, and the residue was purified by flash column chromatography togive the product (0.7 g, 86%) as a tan powder, mp 163-165° C. ¹H NMR(DMSO-d₆, 400 MHz) δ1.3 (s, 9H), 2.16-2.49 (m, 6H), 6.19 (dd, 1H, J=1.8,3.2 Hz), 6.24 (t, 1H, J=3.3 Hz), 6.76 (d, 1H, J=8.1 Hz), 7.09 (dd, 1H,J=1.8, 8.0 Hz), 7.30 (dd, 1H, J=1.8, 3.3 Hz), 7.48 (d, 1H, J=1.8 Hz),10.24 (s, 1H). MS (APCI) m/z 339 [M+H]⁺. Anal. Calcd for C₂₀H₂₂N₂O₃: C,70.99; H, 6.55; N, 8.28. Found: C, 69.51; H, 6.38; N, 7.69.

To a solution of5-(1,2-dihydro-2-oxospiro[cyclobutane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester (0.97 g, 2.9 mmol) in acetonitrile (50 mL) anddichloromethane (5 mL) at −20° C. was added silver nitrate (0.51 g, 3.0mmol). After 20 min, acetyl chloride (0.20 mL, 2.9 mmol) in acetonitrile(3 mL) was added and the solution was allowed to come to roomtemperature. After 24 h, the reaction mixture was diluted withdichloromethane (100 mL) and filtered through celite. The filtrate waspoured into water (100 mL) and the layers were separated. The organiclayer washed with brine (50 mL) and dried over magnesium sulfate. Thesolution was filtered, concentrated in vacuo and the residue waspurified by flash column chromatography on silica gel (40% ethylacetate/hexane) to give the title compound (415 mg, 37%) as a yellowpowder, mp 265° C. (dec.). ¹H NMR (DMSO-d₆; 400 MHz) δ 1.45 (s, 9H),2.17-2.48 (m, 6H), 6.60 (d, 1H, J=4.2 Hz), 6.90 (d, 1H, J=8.1 Hz), 7.35(dd, 1H, J=2.0, 8.1 Hz), 7.46 (d, 1H, J=4.2 Hz), 7.70 (‘d’, 1H, J=1.8Hz), 10.50 (s, 1H). MS (ESI) m/z 382 [M−H]⁻. Anal. Calcd for C₂₀H₂₁N₃O₅:C, 62.65; H, 5.52; N, 10.96. Found: C, 62.58; H, 5.60; N, 10.91.

Example 942-Nitro-5-(1,2-dihydro-2-oxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester

To a solution of5-(1,2-dihydro-2-oxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester (1.5 g, 4.0 mmol) in acetonitrile (50 mL) anddichloromethane (5 mL) at −20° C. was added silver nitrate (0.76 g, 4.5mmol). After 20 min, acetyl chloride (0.30 mL, 4.0 mmol) in acetonitrile(3 mL) was added and the solution was allowed to come to roomtemperature. After 24 h, the reaction mixture was diluted withdichloromethane (100 mL) and filtered through celite. The filtrate waspoured into water (100 mL) and the layers were separated. The organiclayer washed with brine (50 mL) and dried over magnesium sulfate. Thesolution was filtered, concentrated in vacuo and the residue waspurified by flash column chromatography on silica gel (40% ethylacetate/hexane) to give the title compound (650 mg, 41%) as a yellowpowder, mp 150-153° C. ¹H NMR (DMSO-d₆; 400 MHz) δ 1.42 (s, 9H),1.77-2.00 (m, 8H), 6.55 (d, 1H, J=4.2 Hz), 6.93 (d, 1H, J=8.0 Hz), 7.33(dd, 1H, J=1.7, 8.0 Hz), 7.37 (‘d’, 1H, J=1.7 Hz), 7.43 (d, 1H, J=4.2Hz), 10.53 (s, 1H). MS ((−) APCI) m/z 396 [M−H]⁻. Anal. Calcd forC₂₁H₂₃N₃O₅: C, 63.47; H, 5.83; N, 10.57. Found: C, 62.95; H, 5.52; N,10.32.

Example 955-(5-Nitro-1H-pyrrol-2-yl)spiro[cyclobutane-1,3-[3H]indol]-2(1H)-one

2-Nitro-5-(1,2-dihydro-2-oxospiro[cyclobutane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester (350 mg, 0.91 mmol) was placed in a 25 mL roundbottomed flask stoppered with a rubber septum and equipped with nitrogeninlet and a needle to allow gaseous outflow. A vigorous flow of nitrogenwas maintained as the flask was placed in an oil bath and heated to 150°C. After 20 min at this temperature, the flask was removed from the oilbath and allowed to cool. The residue was dissolved in acetone and waspurified by flash column chromatography (40% ethyl acetate/hexane) on apad of silica gel. Further purification by HPLC gave the title compound(100 mg, 39%) as a bright yellow powder, mp 250° C. (dec.); ¹H NMR(DMSO-d₆, 400 MHz) δ 2.18-2.48 (m, 6H), 6.77 (dd, 1H, J=2.4, 4.4 Hz),6.83 (d, 1H, J=8.1 Hz), 7.25 (dd, 1H, J=2.4, 4.3 Hz), 7.73 (dd, 1H,J=2.0, 8.1 Hz), 8.23 (‘d’, 1H, J=1.8 Hz), 10.41 (bs, 1H), 13.13 (s, 1H);MS (ESI) m/z 282 [M−H]. Anal. Calcd. For C₁₅H₁₃N₃O₃: C, 63.60; H, 4.63;N, 14.83. Found: C, 62.59; H, 4.58; N, 14.28.

Example 965-(5-Nitro-1H-pyrrol-2-yl)spiro[cyclopentane-1,3-[3H]indol]-2(1H)-one

2-Nitro-5-(1,2-dihydro-2-oxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester (580 mg, 1.5 mmol) was placed in a 25 mL roundbottomed flask stoppered with a rubber septum and equipped with nitrogeninlet and a needle to allow gaseous outflow. A vigorous flow of nitrogenwas maintained as the flask was placed in an oil bath and heated to 150°C. After 20 min. at this temperature, the flask was removed from the oilbath and allowed to cool. The residue was dissolved in acetone and waspurified by flash column chromatography (40% ethyl acetate/hexane) on apad of silica gel. Further purification by HPLC gave the title compound(300 mg, 67%) as a yellow powder, mp 275° C. (dec.). ¹H NMR (DMSO-d₆,400 MHz) δ 1.78-2.07 (m, 8H), 6.77 (dd, 1H, J=2.4, 4.2 Hz), 6.86 (d, 1H,J=8.2 Hz), 7.24 (dd, 1H, J=2.4, 4.2 Hz), 7.71 (dd, 1H, J=1.8, 8.2 Hz),7.87 (‘d’, 1H, J=1.8 Hz), 10.47 (bs, 1H), 13.12 (s, 1H). MS (ESI) m/z296 [M−H]⁻. Anal. Calcd. For C₁₆H₁₅N₃O₃: C, 64.64; H, 5.09; N, 14.13.Found: C, 63.82; H, 5.20; N, 13.73.

Example 975-(1,2-dihydro-2-oxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester

A solution of 5′-Bromospiro[cyclopentane-1,3′-[3H]indol]-2′(1H)-one (2.0g, 7.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (430 mg, 0.3mmol) in ethylene glycol dimethyl ether (50 mL) was stirred under a flowof nitrogen for 15 min. To the solution was added sequentially1-t-butoxycarbonylpyrrole-2-boronic acid (2.1 g, 9.7 mmol) and potassiumcarbonate (2.4 g, 17 mmol) in water (10 mL). The mixture was heated to80° C. for 3 h and allowed to cool. The reaction mixture was poured intowater (50 mL) and extracted with ethyl acetate (3×50 mL). The organiclayers were combined, washed with brine (30 mL) and dried over magnesiumsulfate. The solution was filtered and concentrated in vacuo.Crystallization from 20% ethyl acetate/hexane gave the product (2.2 g,83%) as a white powder, mp 179-180.5° C. ¹H NMR (DMSO-d₆, 400 MHz) δ1.30 (s, 9H), 1.75-1.98 (m, 8H), 6.16 (dd, 1H, J=1.8, 3.3 Hz), 6.22(‘t’, 1H, J=3.3, 3.3 Hz), 6.79 (d, 1H, J=7.9 Hz), 7.08 (dd, 1H, J=1.8,7.9 Hz), 7.14 (‘d’, 1H, J=1.5 Hz), 7.28 (dd, J=1.9, 3.3 Hz), 10.30 (s,1H); MS (EI) m/z 352 [M⁺]; Anal. Calcd for C₂₁H₂₄N₂O₃: C, 71.57; H,6.86; N, 7.95. Found: C, 71.08; H, 6.83; N, 7.74.

To a solution of5-(1,2-dihydro-2-oxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester (2.2 g, 6.0 mmol) in THF (anhydrous, 25 mL) wasadded at −78° C. chlorosulfonyl isocyanate (0.63 mL, 7.0 mmol). After 90min, dimethylformamide (11 mL, 140 mmol) was added and the reaction wasallowed to warm to room temperature. The reaction mixture was pouredinto water (50 mL) and extracted with ethyl acetate (2×50 mL). Theorganic layers were combined, washed with brine (50 mL), dried overmagnesium sulfate, filtered and concentrated in vacuo. Purification viaflash column chromatography on silica gel (30% ethyl acetate/hexane)gave the title compound (1.7 g, 75%) as white crystals, mp 167-9° C.; ¹HNMR (DMSO-d₆, 400 MHz) δ 1.34 (s, 9H), 1.75-1.98 (m, 8H), 6.39 (d, 1H,J=3.7 Hz), 6.84 (d, 1H, J=7.9 Hz), 7.17 (dd, 1H, J=1.8, 7.9 Hz), 7.28(‘t’, 2H), 10.41 (s, 1H); MS (ESI) m/z 376 [M−H]⁻. Anal. Calcd. forC₂₂H₂₃N₃O₃: C, 70.01; H, 6.14; N, 11.13. Found: C, 69.67; H, 6.38; N,11.04.

Example 985-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-propyl-2-thiophenecarbonitrile

The title compound was prepared in a manner similar to example 69 from5-bromo-4-n-propyl thiophene-2-carbonitrile (1.17 g, 5 mmol),(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol])-5-boronic acid (1.24g, 5 mmol), tetrakis(triphenylphosphine)palladium, potassium carbonate(2.75 g, 21 mmol), water (10 mL), and dimethoxyethane (50 mL) heated atreflux over night, to afford the title compound (0.7 g, 40%): m.p.168-171° C.; ¹H NMR (DMSO-d₆) δ 10.56 (s, 1H), 7.93 (s, 1H) 7.52-7.51(d, 1H, J=1.5 Hz), 7.33-7.29 (dd, 1H, J=1.6 Hz), 7.00-6.96 (d, 1H, J=8.0Hz), 2.62-2.57 (t, 2H), 1.86 (m, 2H), 1.70-1.56 (m, 11H), 0.88-0.84 (t,H); MS m/z (APCI (+)) 351 [M+H]⁺. IR (KBr) 1620, 1700, 2200 cm⁻¹; Anal.Calc. For C₂₁H₂₂N₂OS.½H₂O: C, 70.2; H, 6.39; N, 7.79. Found: C, 70.67;H, 6.34; N, 7.62.

Example 995-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-n-butyl-2-thiophenecarbonitrile

The title compound was prepared in a manner similar to example 69 from5-bromo-4-n-butyl thiophenecarbonitrile¹ (1.24 g, 5.1 mmol),(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol])-5-boronic acid (1.24g, 5.05 mmol), tetrakis(triphenylphosphine)palladium (0.25 g), potassiumcarbonate (2.75 g, 21 mmol), water (10 mL), and dimethoxyethane (50 mL)heated at reflux for 5 hours to afford the title compound (1 g, 54%),m.p. 130-132° C. ¹H NMR (DMSO-d₆) δ 10.56 (s, 1H), 7.92 (s, 1H),7.52-7.51 (d, 1H, J=1.2 Hz), 7.32-7.29 (dd, 1H, J=1.5 Hz), 6.98-6.96 (d,1H, J=8.0 Hz), 2.64-2.59 (t, 2H), 1.99-1.86 (m, 2H), 1.70-1.50 (m, 11H),1.32-1.22 (m, 2H), 0.86-0.82 (t, 3H); MS (APCI (+)) m/z 365 [M+H]⁺; IR(KBr) 1620, 1700; 2200 cm⁻¹; Anal. Calc. For C₂₂H₂₄N₂OS.¼H₂O. C, 71.61;H, 6.69; N, 7.59. Found: C, 71.13; H, 6.61; N, 6.91.

Example 1005-(3-Chlorophenyl)-4-methylspiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

To a −25° C. solution of 4-methyl-2-oxindole (3.0 g, 20.2 mmol) (Tett,1966, 22, 10, 3337-43) in anhydrous THF (100 mL) under N₂ is addedN,N,N′,N′-tetramethylethylenediamine (8.0 mL, 51.0 mmol) followed bydropwise addition of n-butyl lithium (10.0 M in hexanes, 5.1 mL, 51.0mmol). After 30 min. a solution of 1,5-diiopentane (9.2 mL, 61.0 mmol)in 3 (mL) of THF was added and the reaction mixture was allowed to warmto RT and stir for 14 h. The reaction mixture was poured into water,extracted with EtOAc (×2), the combined organic layers were washed withdil. HCl (pH 1), water (×2), dried (MgSO₄) and evaporated. The residuewas purified by column chromatography (SiO₂, ethyl acetate:hexane 1:4)to afford the product (3.2 g, 15 mmol, 74%) as a tan solid: ¹H NMR(CDCl₃) δ 1.2-1.45 (m, 1H), 1.55-1.75 (m, 4H), 1.85-1.95 (d, J=13 Hz,1H), 2.05-2.35 (m, 4H), 2.47 (s, 3H), 6.72 (dd, J=8.1, 1.0 Hz, 1H), 6.95(dd, J=8.1, 8.0 Hz, 1H), 7.32 (dd, J=8.0, 1.0 Hz, 1H), 8.6 (br s, 1H).

5-Bromo-4-methylspiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

A solution of the above oxindole (0.44 g, 2.0 mmol) in CHCl₃ (10 mL)with sodium acetate (0.28 g, 3.4 mmol) is cooled to 0° C. and treatedwith bromine (0.11 mL, 2.0 mmol) in CHCl₃ (4 mL). After 30 min. themixture is warmed to RT and stirred an additional hour. The reactionmixture is poured into sat. sodium hydrogen carbonate solution andextracted with EtOAc (×2), the combined organic layers were washed withwater, sat. sodium hydrogen carbonate solution, water, dried (MgSO₄),and evaporated to give an off-white solid which was purified by columnchromatography (SiO₂, ethyl acetate:hexane 2:4) to afford (0.2 g, 0.7mmol, 35%) of the product: ¹H NMR (CDCl₃) δ 1.2-1.45 (m, 1H), 1.55-1.75(m, 4H), 1.85-1.95 (d, J=13 Hz, 1H), 2.05-2.35 (m, 4H), 2.47 (s, 3H),6.62 (d, J=8.0 Hz, 1H), 7.4 (d, J=8.0 Hz, 1H), 8.47 (br s, 1H).

5-(3-chlorophenyl)-4-methylspiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

A solution of the above 5-bromo-4-methyl-oxindole (0.1 g, 0.34 mmol) andtetrakis(triphenylphosphine) palladium (0.05 g, 0.04 mmol) indimethoxyethane (10 mL) was stirred under N₂ for 20 min. To this mixturewas then added 3-chlorophenylboronic acid (0.065 g, 0.41 mmol) andsodium carbonate (0.1 g, 1.0 mmol) in water (3 mL). The solution wasbrought to reflux for 6 h then cooled to RT, poured into water andextracted with EtOAc (×3). The combined organic extracts were washedwith water, brine, dried (MgSO₄), and evaporated. The residue waspurified by column chromatography (SiO₂, ethyl acetate:hexane 1:3) toafford the subtitled compound (0.077 g, 0.2 mmol, 70%) as a yellowsolid: m.p. 164-165° C.; ¹H NMR (CDCl₃) δ 1.25-1.4 (m, 1H), 1.6-1.7 (m,3H), 1.78 (d, J=12.0 Hz, 2H), 1.9 (d, J=13.0 Hz, 1H), 2.1-2.35 (m, 3H),2.49 (s, 3H), 6.75 (d, J=7.9 Hz, 1H), 7.1 (d, J=7.9 Hz, 1H), 7.15-7.18(m, 1H), 7.26-7.35 (m, 3H), 7.88 (br s, 1H); ¹³C-NMR (CDCl₃) δ 16.71(q), 20.7, 25.5, 29.9 (t), 48.5 (s), 107.1, 127.0, 128.0, 129.4, 129.5,130 (d), 132.2, 133.0, 134.0, 136.6, 140.1, 144, 182.6 (s); MS (EI) m/z326, (M+H)⁺ w/l Cl.

Example 1015-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1H-3-nitropyrrole-2-carbonitrile

To a solution of tert-butyl2-cyano-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-1-carboxylate(0.11 g, 2.6 mmol) in TFA (5 mL) at 0° C. was added silver nitrate (1.1eq, 49 mg, 2.86 mmol). After 5 min the reaction was poured onto ice, DCM(5 mL) was added and the layers were separated. The aqueous layer wasextracted with DCM (3×5 mL) and the combined organic layer washed withbrine, dried over MgSO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel eluting with 40%ethyl acetate/hexane to5-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1H-3-nitropyrrole-2-carbonitrile(20 mg, 21%) as a white solid. ¹H NMR (400 MHz, d₆-DMSO)

1.4-1.9 (10H, m), 6.94 (d, 1H, J=8.1 Hz), 7.47 (dd, 1H, J=8.1, 1.75 Hz),7.73 (s, 1H), 7.75 (d, 1H, J=1.75 Hz), 10.6 (s, 1H), 13.4 (s, 1H). M/z(ES) 335 (M−H)⁻. Anal. calcd for C₁₈H₁₆N₄O₃, C, 64.3, H, 4.79; N, 16.7.Found, C, 62.2, H, 5.20; N, 15.1.

Example 1025-(2-Nitro-1H-pyrrol-3-yl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

According to a procedure described in J. Med. Chem. 1983, 26, p. 800,succinic anhydride (2.0 g, 20 mmol) andspiro[cyclohexane-1,3-[3H]indol]-2(1H)-one (4.03 g, 20 mmol) gave4-oxo-4-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)butanoicacid (100%). ¹H NMR (d₆-DMSO, 300 MHz) δ 1.5-2.0 (m, 10H), 2.56 (t, 1H,J=6 Hz), 3.20 (t, 1H, J=6 Hz), 6.95 (d, 1H, J=8.1 Hz), 7.91 (d, 1H,J=8.1 Hz), 8.0 (s, 1H), 10.7 (s, 1H), 12.1 (s, 1H). MS (EI) m/z 300(M−H)⁻.

According to a procedure described in J. Org. Chem. 1984, p. 38404-oxo-4-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)butanoicacid (5.64 g, 18 mmol) and thallium nitrate gavedimethyl-2-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)succinate(7.95 g, 18 mmol) as a white powder (71%). ¹H NMR (d₆-DMSO, 300 MHz) δ1.44-1.84 (m, 1H), 2.68 (dd, 1H, J=4.97, 16.9 Hz), 3.06 (dd, 1H, J=16.9,10.5 Hz), 3.5 (s, 6H), 4.03 (dd, 1H, J=4.9, 10.5 Hz), 6.78 (d, 1H, J=7.9Hz), 7.07 (d, 1H, J=7.9 Hz), 7.39 (s, 1H), 10.31 (s, 1H). MS (EI) m/z346 (M+H)⁺.

To a solution ofdimethyl-2-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)succinate(2.0 g, 6.0 mmol) in THF (30 mL) was added LiBH₄ (2.5 eq, 0.33 g, 15mmol). The solution was refluxed for 1.5 h, cooled and quenched by thecareful addition of 1N HCl. The aqueous layer was extracted with DCM(3×10 mL) and the combined organic layer washed with brine, dried overMgSO₄ and purified by flash column chromatography on silica gel elutingwith 5% MeOH/ethyl acetate to give of2-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)butan-1,4-diol(78 g, 47%) as a white solid. ¹H NMR (300 MHz, d₆-DMSO) δ 1.53-1.60 (m,1H), 1.72 (m, 2H), 1.93 (m, 7H), 2.69 (m, 1H), 3.26 (m, 2H), 3.46 (t,2H, J=5.8 Hz), 4.35 (t, 1H, J=5.2 Hz), 4.55 (t, 1H, J=5.2 Hz), 6.70 (d,1H, J=7.8 Hz), 6.94 (d, 1H, J=7.8 Hz), 7.03 (s, 1H), 10.2 (s, 1H). M/z(ES) 276 (M+H)⁺. Anal. calcd for C₁₆H₂₁NO₃, C, 96.79, H, 7.69; N, 5.09.Found, C, 70.02, H, 7.64; N, 5.02.

Oxalyl chloride (4 eq, 1.0 mL, 11 mmol) in DCM (40 mL) at −78° C. wastreated with DMSO (8 eq, 1.62 mL, 22 mmol). After 2 min a solution of2-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)butan-1,4-diol(1 eq, 0.78 g, 2.9 mmol) in DMSO:DCM (1:3, 5 mL) was added followed 15min later by addition of triethylamine (18 eq, 7.2 mL, 52 mmol). Thesolution was removed from the cooling bath and allowed to reach roomtemperature. The solution was filtered through celite, concentrated invacuo and redissolved in MeOH (10 mL). A large excess of ammoniumacetate was added and the solution was heated to 60° C. for 1 h thenstored in a refrigerator for 16 h. The solution was partitioned betweenDCM and water. The layers were separated and the aqueous layer wasextracted with DCM (3×10 mL) and the combined organic layer washed withbrine, dried over MgSO₄ and purified by flash column chromatography onsilica gel eluting with 60% ethyl acetate/hexane to give5-(1H-pyrrol-3-yl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one (0.12 g,19%) as a white solid. ¹H NMR (300 MHz, d₆-DMSO) 61.79-1.83 (m, 2H),1.95 (m, 6H), 6.37 (s, 1H), 6.73 (m, 2H), 7.13 (s, 1H), 7.29 (d, 1H, J=8Hz), 10.17 (s, 1H), 10.83 (s, 1H). M/z (ES) 253 (M+H)⁺.

To a solution of5-(1H-pyrrol-3-yl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one (45 mg,0.17 mmol) in DCM:MeCN (1:1, 5 mL) at −40° C. sequentially was addedsilver nitrate (1.1 eq, 32 mg, 0.19 mmol) and a solution of acetylchloride (1.1 eq, 0.01 mL, 0.19 mmol) in MeCN (0.5 mL). After 1 h thecooling bath was removed and the reaction was allowed to stir for 16 h.DCM (20 mL) was added and the suspension was filtered through celite,washed sequentially with sat. aq. NaHCO₃ and brine, dried over MgSO₄ andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel eluting with 40% ethyl acetate/hexane togive5-(2-nitro-1H-pyrrol-3-yl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one (20mg, 40%) as a yellow powder. ¹H NMR (300 MHz, d₆-DMSO)

1.63-1.95 (m, 10J), 6.44 (t, 1H, J=2.69 Hz), 6.97 (d, 1H, J=8.1 Hz),7.22 (t, 1H, J=2.9 Hz), 7.44 (dd, 1H, J=8.1, 1.7 Hz), 7.79 (d, 1H, J=1.4Hz), 9.39 (s, 1H), 11.85 (s, 1H). M/z 310 (M−H)⁻.

Example 103 5-(4-Chlorophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

The title compound was prepared from CAT-817819 (1.9 g, 7.8 mmol) and4-bromochlorobenzene (1.0 g, 5.2 mmol) according to the method forExample 18 to afford the product (0.68 g, 42%) as an off white solid:mp. 226-229° C.; ¹H NMR (DMSO-d₆) δ 10.41 (br s, 1H), 7.68-7.63 (m, 3H),7.49-7.46 (m, 3H), 6.93 (d, 1H, J=8.0 Hz), 1.99-1.82 (m, 2H), 1.76-1.51(m, 8H); MS (EI) m/z 311/313 [M]⁺; C₁₉H₁₈ClON requires C, 73.19; H,5.82; N, 4.49; Found C, 73.13; H, 5.68; N, 4.40.

Example 104 5-(2-Chlorophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

The title compound was prepared from CAT-817819 (1.9 g, 7.8 mmol) and2-bromochlorobenzene (1.0 g, 5.2 mmol) according to the method forExample 18 to afford the title compound (0.68 g, 42%) as an off whitesolid: mp. 174-175° C.; ¹H NMR (DMSO-d₆) δ 10.43 (br s, 1H), 7.56-7.52(m, 2H), 7.43-7.33 (m, 3H), 7.25 (dd, 1H, J=8.0 and 1.7 Hz), 6.93 (d,1H, J=8.0 Hz), 1.92-1.79 (m, 2H) and 1.77-1.43 (M, 8H); MS (EI) m/z311/313 [M]⁺; Anal. Calc. For C₁₉H₁₈ClON: C, 73.19; H, 5.82; N, 4.49;Found C, 73.10; H, 5.86; N, 4.30.

Example 1055-(1,2-Dihydro-2-oxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-2-furancarbonitrile

The title compound was prepared from CAT-830083 (0.9 g, 3.9 mmol) and5-cyano-furancarbonitrile (0.5 g, 2.6 mmol) according to the method forExample 18 to afford the title compound (0.35, 49%) as an off whitesolid: mp. 193-194° C.; ¹H NMR (DMSO-d₆) δ 10.55 (br s, 1H), 7.69-7.63(m, 3H), 7.15 (d, 1H, J=3.8 Hz), 6.92 (d, 1H, J=8.1 Hz), 2.00-1.83 (m,8H); MS (ESI (−)) m/z 277 [M−H]⁻. Anal. Calc. For C₁₇H₁₄N₂O₂: C, 73.73;H, 5.07; N, 10.07; Found C, 73.01; H, 4.98; N, 9.69.

All publications cited in this specification are incorporated herein byreference herein. While the invention has been described with referenceto a particularly preferred embodiment, it will be appreciated thatmodifications can be made without departing from the spirit of theinvention. Such modifications are intended to fall within the scope ofthe appended claims.

1. A method of inducing contraception in a mammal, the method comprisingadministering to a mammal in need thereof a pharmaceutically effectiveamount of a compound of the structure:

wherein: R₁ and R₂ form a double bond to C(CH₃)₂, C(cycloalkyl), O, orC(cycoether); R₃ is selected from the group consisting of H, OH, NH₂, C₁to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₆ alkenyl, alkynyl,substituted alkynyl, and COR^(A); R^(A) is selected from the groupconsisting of H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, C₁ to C₃alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, andsubstituted C₁ to C₃ aminoalkyl; R₄ is selected from the groupconsisting of H, halogen, CN, NH₂, C₁ to C₆ alkyl, substituted C₁ to C₆alkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆aminoalkyl, and substituted C₁ to C₆ aminoalkyl; R⁵ is a five memberedring of the structure:

wherein: U is O, S, or NR⁶, R⁶ is H, C₁ to C₃ alkyl, or C₁ to C₄CO₂alkyl, X′ is selected from the group consisting of halogen, CN, NO₂,C₁ to C₃ alkyl and C₁ to C₃ alkoxy; with the proviso that when X′ is CN,U is not NR⁶; Y′ is selected from the group consisting of H, F, CN, NO₂,and C₁ to C₄ alkyl; or a pharmaceutically acceptable salt thereof.
 2. Amethod of inducing contraception in a mammal, the method comprisingadministering to a mammal in need thereof a pharmaceutically effectiveamount of a compound of the structure:

wherein: R₁ and R₂ form a double bond to C(CH₃)₂, C(cycloalkyl), O, orC(cycloether); R₃ is selected from the group consisting of H, OH, NH₂,C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₆ alkenyl, alkynyl,substituted alkynyl, and COR^(A); R^(A) is selected from the groupconsisting of H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, C₁ to C₃alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, andsubstituted C₁ to C₃ aminoalkyl; R₄ is selected from the groupconsisting of H, halogen, CN, NH₂C₁ to C₆ alkyl, substituted C₁ to C₆alkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆aminoalkyl, and substituted C_(1 to C) ₆ aminoalkyl; R⁵ is a sixmembered ring of the structure:

wherein: X¹ is CX²; X² is halogen, CN or NO₂; or a pharmaceuticallyacceptable salt thereof.
 3. A method of inducing contraception in amammal, the method comprising administering to a mammal in need thereofa pharmaceutically effective amount of a compound of the structure:

wherein: R₁ and R₂ form a double bond to C(CH₃)₂, C(cycloalkyl), O, orC(cycloether); R₃ is selected from the group consisting of H, OH, NH₂,C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₆ alkenyl, alkynyl,substituted alkynyl, and COR^(A); R^(A) is selected from the groupconsisting of H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, C₁ to C₃alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, andsubstituted C₁ to C₃ aminoalkyl; R₄ is selected from the groupconsisting of H, halogen, CN, NH₂, C₁ to C₆ alkyl, substituted C₁ to C₆alkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆aminoalkyl, and substituted C₁ to C₆ aminoalkyl; R⁵ is selected from thegroup consisting of a) and b): a) a five or six membered heterocyclicring having in its backbone 1, 2, or 3 heteroatoms selected from thegroup consisting of O, S, SO, SO₂ and NR⁶ and containing one or twoindependent substituents selected from the group consisting of H,halogen, CN, NO₂, C₁ to C₃ alkyl, C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl,COR^(D), and NR^(E)COR^(D); R^(D) is H, C₁ to C₃ alkyl, substituted C₁to C₃ alkyl, aryl, substituted aryl, C₁ to C₃ alkoxy, substituted C₁ toC₃ alkoxy, C₁ to C₃ aminoalkyl, or substituted C₁ to C₃ aminoalkyl;R^(E) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃ alkyl; R⁶ is H or C₁to C₃ alkyl; and b) an indol-4-yl, indol-7-yl or benzo-2-thiophenemoiety, the moiety being optionally substituted by from 1 to 3substituents selected from the group consisting of halogen, lower alkyl,CN, NO₂, lower alkoxy, and CF₃; or a pharmaceutically acceptable saltthereof.
 4. A method of hormone replacement therapy, the methodcomprising administering to a mammal in need thereof a pharmaceuticallyeffective amount of a compound the structure:

wherein: R₁ and R₂ form a double bond to C(CH₃)₂, C(cycloalkyl), O, orC(cycloether); R₃ is selected from the group consisting of H, OH, NH₂,C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₆ alkenyl, alkynyl,substituted alkynyl, and COR^(A); R^(A) is selected from the groupconsisting of H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, C₁ to C₃alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, andsubstituted C₁ to C₃ aminoalkyl; R₄ is selected from the groupconsisting of H, halogen, CN, NH₂, C₁ to C₆ alkyl, substituted C₁ to C₆alkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, C₁ to C₆aminoalkyl, and substituted C₁ to C₆ aminoalkyl; R⁵ is selected from thegroup consisting of a) and b): a) a five or six membered heterocyclicring having in its backbone 1, 2, or 3 heteroatoms selected from thegroup consisting of O, S, SO, SO₂ and NR⁶ and containing one or twoindependent substituents selected from the group consisting of H,halogen, CN, NO₂, C₁ to C₃ alkyl, C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl,COR^(D), and NR^(E)COR^(D); R^(D) is H, C₁ to C₃ alkyl, substituted C₁to C₃ alkyl, aryl, substituted aryl, C₁ to C₃ alkoxy, substituted C₁ toC₃ alkoxy, C₁ to C₃ aminoalkyl, or substituted C₁ to C₃ aminoalkyl;R^(E) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃ alkyl; R⁶ is H or C₁to C₃ alkyl; and b) an indol-4-yl, indol-7-yl or benzo-2-thiophenemoiety, the moiety being optionally substituted by from 1 to 3substituents selected from the group consisting of halogen, lower alkyl,CN, NO₂, lower alkoxy, and CF₃; or a pharmaceutically acceptable saltthereof.
 5. A method of inducing contraception or hormone replacementtherapy in a mammal, the method comprising administering to a mammal inneed thereof a pharmaceutically effective amount of a compound of theformula:

wherein: R₁ and R₂ are selected from the group consisting of H, alkyl,substituted alkyl, OH, O(alkyl), O(substituted alkyl), OAc, aryl,substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl,alkylheteroaryl, 1-propynyl, and 3-propynyl; R₃ is selected from thegroup consisting of H, OH, NH₂, C₁ to C₆ alkyl, substituted C₁ to C₆alkyl, C₃ to C₆ alkenyl, alkynyl, substituted alkynyl, and COR^(A);R^(A) is selected from the group consisting of H, C₁ to C₃ alkyl,substituted C₁ to C₃ alkyl, C₁ to C₃ alkoxy, substituted C₁ to C₃alkoxy, C₁ to C₃ aminoalkyl, and substituted C₁ to C₃ aminoalkyl; R₄ isselected from the group consisting of H, halogen, CN, NH₂, C₁ to C₆alkyl, substituted C₁ to C₆ alkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆alkoxy, C₁ to C₆ aminoalkyl, and substituted C₁ to C₆ aminoalkyl; R⁵ isselected from the group consisting of a), b), and c): a) a five memberedheterocyclic ring having in its backbone 1, 2, or 3 heteroatoms selectedfrom the group consisting of O, S, SO, SO₂ and NR₆ and containing one ortwo independent substituents selected from the group consisting of H,halogen, CN, NO₂, C₁ to C₃ alkyl, C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl,COR^(D), and NR^(E)COR^(D); with the proviso that when the five-memberedheterocyclic ring having in its backbone one NR⁶ heteroatom is attachedat the 2-position on said ring, the CN substituent is attached at the1-,3-, 4-, or 5-position of said ring; b) a six membered hetcrocyclicring having in its backbone 1 or 2 heteroatoms selected from the groupconsisting of O, S, SO, SO₂ and NR₆ and containing one or twoindependent substituents selected from the group consisting of H,halogen, CN, NO₂, C₁ to C₃ alkyl, C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl,COR^(D), and NR^(E)COR^(D); R^(D) is H, C₁ to C₃ alkyl, substituted C₁to C₃ alkyl, aryl, substituted aryl, C₁ to C₃ alkoxy, substituted C₁ toC₃ alkoxy, C₁ to C₃ aminoalkyl, or substituted C₁ to C₃ aminoalkyl;R^(E) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃ alkyl; R⁶ is H or C₁to C₃ alkyl; and c) an indol-4-yl, indol-7-yl or benzo-2-thiophenemoiety, the moiety being optionally substituted by from 1 to 3substituents selected from the group consisting of halogen, lower alkyl,CN, NO₂, lower alkoxy, and CF₃; or a pharmaceutically acceptable saltthereof.
 6. A method of inducing contraception or hormone replacementtherapy in a mammal, the method comprising administering to a mammal inneed thereof a pharmaceutically effective amount of a compound selectedfrom the group consisting of5-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-4-methylthiophene-2-carbonitrile;4-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-furan-2-carbonitrile;5-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-furan-2-carbonitrile;2-(3 ,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2-nitro-pyrrole;5-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-thiophene-2-carbonitrile;and 3,3-Dimethyl-5-(5-nitro-thiophene-2-yl)-1,3-dihydro-indol-2-one; ora pharmaceutically acceptable salt thereof.
 7. A method of inducingcontraception in a mammal, the method comprising administering to amammal in need thereof a pharmaceutically effective amount of a compoundof the formula:

wherein: R₁ and R₂ are selected from the group consisting of H, alkyl,substituted alkyl, OH, O(alkyl), O(substituted alkyl), OAc, aryl,substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl,alkylheteroaryl, 1-propynyl, and 3-propynyl; R₃ is selected from thegroup consisting of H, OH, NH₂, C₁ to C₆ alkyl, substituted C₁ to C₆alkyl, C₃ to C₆ alkenyl, alkynyl, substituted alkynyl, and COR^(A);R^(A) is selected from the group consisting of H, C₁ to C₃ alkyl,substituted C₁ to C₃ alkyl, C₁ to C₃ alkoxy, substituted C₁ to C₃alkoxy, C₁ to C₃ aminoalkyl, and substituted C₁ to C₃ aminoalkyl; R₄ isselected from the group consisting of H, halogen, CN, NH₂, C₁ to C₆alkyl, substituted C₁ to C₆ alkyl, C₁ to C₆ alkoxy substituted C₁ to C₆alkoxy, C₁ to C₆ aminoalkyl, and substituted C₁ to C₆ aminoalkyl; R⁵ isa six membered ring with the structure shown below:

wherein: X¹ is N; or pharmaceutically acceptable salt thereof.
 8. Amethod of hormone replacement therapy, the method comprisingadministering to a mammal in need thereof a pharmaceutically effectiveamount of a compound of the formula:

wherein: R₁ and R₂ are selected from the group consisting of H, alkyl,substituted alkyl, OH, O(alkyl), O(substituted alkyl), OAc, aryl,substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl,alkylheteroaryl, 1-propynyl, and 3-propynyl; R₃ is selected from thegroup consisting of H, OH, NH₂, C₁ to C₆ alkyl, substituted C₁ to C₆alkyl, C₃ to C₆ alkenyl, alkynyl, substituted alkynyl, and COR^(A);R^(A) is selected from the group consisting of H, C₁ to C₃ alkyl,substituted C₁ to C₃ alkyl, C₁ to C₃ alkoxy, substituted C₁ to C₃alkoxy, C₁ to C₃ aminoalkyl, and substituted C₁ to C₃ aminoalkyl; R₄ isselected from the group consisting of H, halogen, CN, NH₂, C₁ to C₆alkyl, substituted C₁ to C₆ alkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆alkoxy, C₁ to C₆ aminoalkyl, and substituted C₁ to C₆ aminoalkyl; R⁵ isa six membered ring with the structure shown below:

wherein: X¹ is N; or pharmaceutically acceptable salt thereof.